Thiophene derivatives

ABSTRACT

Compounds of the formula I 
     
       
         
         
             
             
         
       
         
         
           
             in which R 1  denotes A, Ar, Cyc, Het, COA or CN, R 2  denotes SO 2 A, SOA, SA, SO 2 NHA, SO 2 NA 2 , S(═NH,═O)A, S(═NH) 2 A, NO 2 , Hal, CN, A, Het 1 , COOH or COOA, R 3  denotes H or Hal, R 4  denotes H or Hal, n denotes 1, 2 or 3, A denotes unbranched or branched alkyl having 1-6 C-atoms, Cyc denotes cyclic alkyl with 3 to 7 C-atoms, Ar denotes phenyl, Het denotes a mono- or bicyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O, and/or S atoms, Het 1  denotes a mono- or bicyclic aromatic, unsaturated or saturated heterocycle having 1 to 4 N, O, and/or S atoms, and Hal denotes F, Cl, Br, or I, are inhibitors of HIF-2α, and can be employed for the treatment of diseases such as cancer.

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to thiophene derivatives which inhibitHIF-2α (Hypoxia-Inducible Factor). The compounds of this invention aretherefore useful in treating diseases such as cancer.

The present invention also provides methods for preparing thesecompounds, pharmaceutical compositions comprising these compounds, andmethods of treating diseases utilizing pharmaceutical compositionscomprising these compounds.

An adequate supply of oxygen to tissues is essential in maintainingmammalian cell function and physiology. A deficiency in oxygen supply totissues is a characteristic of a number of pathophysiologic conditionsin which there is insufficient blood flow to provide adequateoxygenation, for example, ischemic disorders, cancer, andatherosclerosis. The hypoxic (low oxygen) environment of tissuesactivates a signaling cascade that drives the induction or repression ofthe transcription of a multitude of genes implicated in events such asangiogenesis (neo-vascularization), glucose metabolism, and cellsurvival/death. A key to this hypoxic transcriptional response lies inthe transcription factors, the hypoxia-inducible factors (HIF).

HIFs are disregulated in a vast array of cancers throughhypoxia-dependent and independent mechanisms and expression isassociated with poor patient prognosis. Hypoxia inducible factors(HIFs), including HIF-1α and HIF-2α, are transcription factors thatmediate cellular responses to diminished oxygen supply. These proteinsbecome stabilized under hypoxia (low oxygen) and subsequently activatethe expression of genes to facilitate cell survival and proliferation.HIF proteins are activated in many types of cancers and have beenimplicated in cancer initiation, progression, and metastasis. The roleof HIF-2α is particularly important in clear cell renal cell carcinoma(ccRCC). In the majority of ccRCC tumors, the tumor suppressor vonHippel-Lindau protein (pVHL) that targets HIF-2α for degradation isinactivated, leading to the accumulation of HIF-2α and the transcriptionof genes that drive kidney cancer tumorigenesis. Certain cancersincluding renal cell carcinoma show high levels of HIF-2α and adependency on HIF-2α signaling.

HIF-2α protein has been detected in various human tumors of the bladder,breast, colon, liver, ovaries, pancreas, prostate, and kidney as well astumor-associated macrophages.

Compounds of this invention show high activity against HIF-2α inmultiple relevant settings including biochemical, biophysical andcellular assays.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow active agents such as anti IgM to induce a cellularresponse such as expression of a surface marker, usually between aboutone hour and one week. In vitro testing can be carried out usingcultivated cells from blood or from a biopsy sample. The amount ofsurface marker expressed is assessed by flow cytometry using specificantibodies recognising the marker.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

PRIOR ART

Other HIF-2α inhibitors for the treatment of cancer are described in WO2018/031680 A1, WO 2015/035223 A1, WO 2016/145045 A1, WO 2016/145032 A1,WO 2016/144825 A1, WO 2016/144826 A1 and WO 2016/168510 A1.

Preclinical on-target efficacies studies of a HIF-2α antagonist aredescribed by H. Cho et al. Nature, Vol. 539, 2016, 107-122(doi:10.1038/nature19795) and by W. Chen et al. Nature, Vol. 539, 2016,112-130 (doi:10.1038/nature19796).

A review on HIF-2α targeting approaches is described by S. E. WilkinsChem Med Chem, 2016, 11, 773-786.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R¹ denotes A, Ar, Cyc, Het, COA or CN,-   R² denotes SO₂A, SOA, SA, SO₂NHA, SO₂NA₂, S(═NH,═O)A, S(═NH)₂A, NO₂,    Hal, CN, A, Het¹, COOH or COOA,-   R³ denotes H or Hal,-   R⁴ denotes H or Hal,-   A denotes unbranched or branched alkyl having 1-6 C-atoms, in which    1-7 H atoms may be replaced by OH, F, Cl and/or Br and/or in which    one or two non-adjacent CH₂ groups may be replaced by O and/or NH    groups,-   Cyc cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms,-   Ar denotes phenyl, which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, [C(R⁵)₂]_(p)OR⁵, O[C(R⁵)₂]_(p)OR⁵,    [C(R⁵)₂]_(p)N(R⁵)₂, O[C(R⁵)₂]_(p)N(R⁵)₂, [C(R⁵)₂]_(p)Het¹, NO₂, CN,    [C(R⁵)₂]_(p)COOR⁵, O[C(R⁵)₂]_(p)COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A,    SO₂N(R⁵)₂, S(O)₂A, COHet¹, O[C(R⁵)₂]_(p)Het¹, NHCOOA, NHCON(R⁵)₂,    NHCOO[C(R⁵)₂]_(m)N(R⁵)₂, NHCOO[C(R⁵)₂]_(p)Het¹,    NHCONH[C(R⁵)₂]_(m)N(R⁵)₂, NHCONH[C(R⁵)₂]_(p)Het¹,    OCONH[C(R⁵)₂]_(m)N(R⁵)₂, OCONH[C(R⁵)₂]_(p)Het¹, S(O)₂Het¹, and/or    COA,-   Het denotes a mono- or bicyclic aromatic, unsaturated or saturated    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by Hal, A, NH₂, NHA,    NA₂, COOH, COOA, CONH₂, CONHA, CONA₂, CONHAr, S(O)_(m)A, NHCH₂Ar¹,    CN, OH and/or OA,-   Het¹ denotes a mono- or bicyclic aromatic, unsaturated or saturated    heterocycle having 1 to 4 N, O and/or S atoms, which may be    unsubstituted or mono-, di- or trisubstituted by Hal, A, COOA, NH₂,    NHA and/or NA₂,-   Ar¹ denotes phenyl which is unsubstituted or mono-, di- or    trisubstituted by Hal, A, OH and/or OA,-   R⁵ denotes H or alkyl with 1, 2, 3 or 4 C-atoms,-   Hal denotes F, Cl, Br or I,-   n denotes 1, 2 or 3,-   m denotes 1, 2 or 3,-   p denotes 0, 1, 2, 3 or 4,

and pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds.

Moreover, the invention relates to pharmaceutically acceptablederivatives of compounds of formula I.

The term solvates of the compounds is used to describe adductions ofinert solvent molecules onto the compounds which form owing to theirmutual attractive force. Solvates are, for example, mono- or dihydratesor alkoxides.

It is understood, that the invention also relates to the solvates of thesalts.

The term pharmaceutically acceptable derivatives is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound of formula I that can hydrolyze, oxidize, orotherwise react under biological conditions (in vitro or in vivo) toprovide an active compound, particularly a compound of formula I.Examples of prodrugs include, but are not limited to, derivatives andmetabolites of a compound of formula I that include biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. In certainembodiments, prodrugs of compounds with carboxyl functional groups arethe lower alkyl esters of the carboxylic acid. The carboxylate estersare conveniently formed by esterifying any of the carboxylic acidmoieties present on the molecule. Prodrugs can typically be preparedusing well-known methods, such as those described by Burger's MedicinalChemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001,Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985,Harwood Academic Publishers Gmfh).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically acceptable salts, solvates, tautomers andstereoisomers thereof, characterised in that

a)

a compound of the formula II

in which R², R³, R⁴ and n have the meanings indicated in Claim 1 and Xis F, Cl, Br or I,

is reacted

with a compound of formula III

L-R¹  III

in which R¹ has the meanings indicated in Claim 1,

and L denotes H, a boronic acid or a boronic acid ester group,

or

b)

a compound of the formula IV

in which R¹, R², R³, R⁴ and n have the meanings indicated in Claim 1,

is reacted with NaBH₄

and/or

a base or acid of the formula I is converted into one of its salts.

Above and below, the radicals R¹, R², R³, R⁴ and n have the meaningsindicated for the formula I, unless explicitely stated otherwise.

A denotes alkyl, this is unbranched (linear) or branched, and has 1, 2,3, 4, 5, 6, 7 or 8 C atoms. A preferably denotes methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore alsopentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoro-ethyl.

Moreover, A denotes preferably CH₂CH₃, CH₂CH₂OH or CH₂CH₂OCH₃.

Moreover, A denotes preferably unbranched or branched alkyl having 1-6C-atoms, in which 1-5 H atoms may be replaced by OH and/or F.

R¹ preferably denotes Ar or Het.

R² preferably denotes SO₂A, most preferably SO₂CH₃.

R³ preferably denotes H or F.

R⁴ preferably denotes H or F.

Cyc denotes cycloprolyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, pyrrolopyridinyl, purinyl, furtherpreferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl,azabicyclo[3.2.1]-octyl or dibenzo-furanyl.

The heterocyclic radicals may also be partially or fully hydrogenated.

Irrespective of further substitutions, Het can thus also denote, forexample, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2-or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl,tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetra-hydro-1-,-2-,-3-,-4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Irrespective of further substitutions, Het¹ denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, pyrrolopyridinyl, purinyl, furtherpreferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl,azabicyclo[3.2.1]-octyl or dibenzo-furanyl.

The heterocyclic radicals may also be partially or fully hydrogenated.

Irrespective of further substitutions, Het¹ can thus also denote, forexample, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2-or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazoyl, 1,4-dihydro-1-, -2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl,tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-,-4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes a monocyclic aromatic heterocycle having 1 to 4N, O and/or S atoms, which may be unsubstituted or mono-, di- ortrisubstituted by Hal, A, CN, OH and/or OA.

Het particularly preferably denotes pyrrolyl, pyrazolyl, imidazolyl,pyridinyl or pyrimidinyl, each of which may be unsubstituted or mono-,di- or trisubstituted by Hal, A and/or CN.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butyl-phenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-nitrophenyl, o-, m- or p-aminophenyl, o-, m- orp-(N-methylamino)phenyl, o-, m- or p-(N-methyl-aminocarbonyl)phenyl, o-,m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethyl-aminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-carboxy-phenyl, o-, m- orp-methoxycarbonylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-(benzylamino)phenyl furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl,3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-,2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar particularly preferably denotes phenyl which is unsubstituted ormono-, di- or trisubstituted by Hal and/or CN.

Particularly preferred compounds of formula I are

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ik, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R¹ denotes Ar or Het;-   in Ib R² denotes SO₂A;-   in Ie R³ denotes H or F,    -   R⁴ denotes H or F;-   in If A denotes unbranched or branched alkyl having 1-6 C-atoms, in    which 1-5 H atoms may be replaced by OH and/or F;-   in Ig Ar denotes phenyl, which is unsubstituted or mono-, di- or    trisubstituted by Hal and/or CN;-   in Ih Het denotes a monocyclic aromatic heterocycle having 1 to 4 N,    O and/or S atoms, which may be unsubstituted or mono-, di- or    trisubstituted by Hal, A, CN, OH and/or OA;-   in Ii Het denotes pyrrolyl, pyrazolyl, imidazolyl, pyridinyl or    pyrimidinyl, each of which may be unsubstituted or mono-, di- or    trisubstituted by Hal, OH, OA, A and/or CN;-   in Ij R¹ denotes Ar or Het;    -   R² denotes SO₂A,    -   R³ denotes H or Hal,    -   R⁴ denotes H or Hal,    -   A denotes denotes unbranched or branched alkyl having 1-6        C-atoms, in which 1-5 H atoms may be replaced by OH and/or F,    -   Ar denotes phenyl, which is unsubstituted or mono-, di- or        trisubstituted by Hal and/or CN,    -   Het denotes a monocyclic aromatic heterocycle having 1 to 4 N, O        and/or S atoms, which may be unsubstituted or mono-, di- or        trisubstituted by Hal, A, CN, OH and/or OA,    -   Hal denotes F, Cl, Br or I,    -   n denotes 1, 2 or 3;    -   and pharmaceutically acceptable salts, tautomers and        stereoisomers thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

The starting compounds of the formula II and III are generally known. Ifthey are novel, however, they can be prepared by methods known per se.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a compound of the formula III.

In the compounds of the formula III, L preferably denotes H,

This coupling is generally carried out at elevated temperature using apalladium catalyst, a base and an inert solvent. An overview ofcatalysts and reaction conditions can be found in the literature [see,for instance, S. Kotha et al., Tetrahedron 2002, 58, 9633-9695; T. E.Barder et al., J. Am. Chem. Soc. 2005, 127, 4685-4696]. The preferredcatalyst in this reaction is tetrakis(triphenylphosphine)-palladium(0)or PdCl₂(PPh₃)₂. The preferred base is sodium carbonate employed as anaqueous solution. The reaction is carried out in organic solvents thatare inert under the reaction conditions, such as 1,4-dioxane, ACN, DMFor DMSO, or in water or in mixtures of these solvents. Preferably, thereaction is carried out in a mixture of 1,4-dioxane and water or ACN andwater. The reaction is generally performed at temperatures between +100°C. and +250° C., preferably at +110° C. to +150° C. Heating ispreferably effected by a singlemode microwave device. The reactions areusually run under an inert gas atmosphere, preferably under argon.

Moreover, compounds of the formula I can preferably be obtained byreacting a compound of the formula IV with a complex hydride such asNaBH₄ in an inert solvent such as MeOH or THF. The reaction is generallyperformed at temperatures between 0° C. and 75° C., preferably at 10° C.to 40° C.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, formate,galacterate (from mucic acid), galacturonate, glucoheptanoate,gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate,heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate,lactate, lactobionate, malate, maleate, malonate, mandelate,metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(II), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion ex-changer resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylamino-ethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, TEA,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Isotopes

There is furthermore intended that a compound of the formula I includesisotope-labelled forms thereof. An isotope-labelled form of a compoundof the formula I is identical to this compound apart from the fact thatone or more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,fluorine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I or apharmaceutically acceptable salt of either which contains one or more ofthe above-mentioned isotopes and/or other isotopes of other atoms isintended to be part of the present invention. An isotope-labelledcompound of the formula I can be used in a number of beneficial ways.For example, an isotope-labelled compound of the formula I into which,for example, a radioisotope, such as ³H or ¹⁴C, has been incorporated issuitable for medicament and/or substrate tissue distribution assays.These radioisotopes, i.e. tritium (³H) and carbon-14 (¹⁴C), areparticularly preferred owing to simple preparation and excellentdetectability. Incorporation of heavier isotopes, for example deuterium(²H), into a compound of the formula I has therapeutic advantages owingto the higher metabolic stability of this isotope-labelled compound.Higher metabolic stability translates directly into an increased in vivohalf-life or lower dosages, which under most circumstances wouldrepresent a preferred embodiment of the present invention. Anisotope-labelled compound of the formula I can usually be prepared bycarrying out the procedures dis-closed in the synthesis schemes and therelated description, in the example part and in the preparation part inthe present text, replacing a non-isotope-labelled reactant by a readilyavailable isotope-labelled reactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus cause a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a compoundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimise pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative meta-bolism. Significant improvements inthe pharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t½), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favourable and accuratedetermination of the extent of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favourable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically acceptable salts,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and pharmaceutically salts, tautomers andstereoisomers thereof can also be administered in the form of liposomedelivery systems, such as, for example, small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from various phospholipids, such as, for example, cholesterol,stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, tautomers andstereoisomers thereof can also be delivered using monoclonal antibodiesas individual carriers to which the compound molecules are coupled. Thecompounds can also be coupled to soluble polymers as targeted medicamentcarriers. Such polymers may encompass polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidophenol,polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine,substituted by palmitoyl radicals. The compounds may furthermore becoupled to a class of biodegradable polymers which are suitable forachieving controlled release of a medicament, for example polylacticacid, poly-epsilon-caprolactone, polyhydroxybutyric acid,polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylatesand crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention is generally in the range from 0.1 to 100 mg/kg of body weightof the recipient (mammal) per day and particularly typically in therange from 1 to 10 mg/kg of body weight per day. Thus, the actual amountper day for an adult mammal weighing 70 kg is usually between 70 and 700mg, where this amount can be administered as a single dose per day orusually in a series of part-doses (such as, for example, two, three,four, five or six) per day, so that the total daily dose is the same. Aneffective amount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound according to the invention per se. It can beassumed that similar doses are suitable for the treatment of otherconditions mentioned above.

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically acceptable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically acceptable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios,-    and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically acceptable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

“Treating” as used herein, means an alleviation, in whole or in part, ofsymptoms associated with a disorder or disease, or slowing, or haltingof further progression or worsening of those symptoms, or prevention orprophylaxis of the disease or disorder in a subject at risk fordeveloping the disease or disorder.

The term “effective amount” in connection with a compound of formula (I)can mean an amount capable of alleviating, in whole or in part, symptomsassociated with a disorder or disease, or slowing or halting furtherprogression or worsening of those symptoms, or preventing or providingprophylaxis for the disease or disorder in a subject having or at riskfor developing a disease disclosed herein, such as inflammatoryconditions, immunological conditions, cancer or metabolic conditions.

In one embodiment an effective amount of a compound of formula (I) is anamount that inhibits HIF-2α in a cell, such as, for example, in vitro orin vivo. In some embodiments, the effective amount of the compound offormula (I) inhibits HIF-2α in a cell by 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90% or 99%, compared to the activity of HIF-2α in an untreatedcell. The effective amount of the compound of formula (I), for examplein a pharmaceutical composition, may be at a level that will exercisethe desired effect; for example, about 0.005 mg/kg of a subject's bodyweight to about 10 mg/kg of a subject's body weight in unit dosage forboth oral and parenteral administration.

Use

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, especially for humans, in the treatment of cancer.

The present invention encompasses the use of the compounds of theformula I and/or pharmaceutically acceptable salts, tautomers andstereoisomers thereof for the preparation of a medicament for thetreatment or prevention of cancer.

Moreover, the present invention encompasses the compounds for use of theformula I and/or pharmaceutically acceptable salts, tautomers andstereoisomers thereof for treatment or prevention of cancer.

Also encompassed is the use of the compounds of the formula I and/orpharmaceutically acceptable salts, tautomers and stereoisomers thereoffor the preparation of a medicament for the treatment or prevention of aHIF-2α-induced disease or a HIF-2α-induced condition in a mammal, inwhich to this method a therapeutically effective amount of a compoundaccording to the invention is administered to a sick mammal in need ofsuch treatment. The therapeutic amount varies according to the specificdisease and can be determined by the person skilled in the art withoutundue effort.

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, for the use for thetreatment of diseases in which the inhibition, regulation and/ormodulation inhibition of HIF-2α plays a role.

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, for the use for theinhibition of HIF-2α.

Representative cancers that compounds of formula I are useful fortreating or preventing include, but are not limited to, cancer of thehead, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx,chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder,uterine, cervix, breast, ovaries, testicles or other reproductiveorgans, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas,brain, central nervous system, solid tumors and blood-borne tumors.

Moreover, representative cancers that compounds of formula I are usefulfor treating or preventing include glioblastoma, renal cell carcinoma(RCC) and clear cell renal cell carcinoma (ccRCC).

Moreover, the present invention encompasses the compounds for use of theformula I and/or pharmaceutically acceptable salts, tautomers andstereoisomers thereof for treatment or prevention of von Hippel-Lindau(VHL) disease.

Moreover, the present invention encompasses the compounds for use of theformula I and/or pharmaceutically acceptable salts, tautomers andstereoisomers thereof for treatment or prevention of a cardiovasculardisease.

Preferably, the present invention relates to a method of treating cancercomprising administering to a subject in need thereof an effectiveamount of a compound of formula I according to the invention.

Particularly preferable, the present invention relates to a methodwherein the disease is a cancer, wherein administration is simultaneous,sequential or in alternation with administration of at least one otheractive drug agent.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anticancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaI, conventional surgery or radiotherapy or medicinal therapy. Suchmedicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating Agents

such as altretamine, bendamustine, busulfan, carmustine, chlorambucil,chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan,tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine,ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine,carboquone;

apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman,trofosfamide, uramustine, TH-302⁴, VAL-083⁴;

Platinum Compounds

such as carboplatin, cisplatin, eptaplatin, miriplatine hydrate,oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

lobaplatin, nedaplatin, picoplatin, satraplatin;

DNA Altering Agents

such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine,trabectedin, clofarabine;

amsacrine, brostallicin, pixantrone, laromustine^(1,3);

Topoisomerase Inhibitors

such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide,topotecan; amonafide, belotecan, elliptinium acetate, voreloxin;

Microtubule Modifiers

such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel,vinblastine, vincristine, vinorelbine, vindesine, vinflunine;

fosbretabulin, tesetaxel;

Antimetabolites

such as asparaginase³, azacitidine, calcium levofolinate, capecitabine,cladribine, cytarabine, enocitabine, floxuridine, fludarabine,fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine,pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur;

doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur^(2,3),trimetrexate;

Anticancer Antibiotics

such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin,levamisole, miltefosine, mitomycin C, romidepsin, streptozocin,valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin;

aclarubicin, peplomycin, pirarubicin;

Hormones/Antagonists

such as abarelix, abiraterone, bicalutamide, buserelin, calusterone,chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolonefluoxymesterone, flutamide, fulvestrant, goserelin, histrelin,leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide,octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa,toremifene, trilostane, triptorelin, diethylstilbestrol;

acolbifene, danazol, deslorelin, epitiostanol, orteronel,enzalutamide^(1,3);

Aromatase Inhibitors

such as aminoglutethimide, anastrozole, exemestane, fadrozole,letrozole,

testolactone;

formestane;

Small Molecule Kinase Inhibitors

such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib,nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib,vandetanib, vemurafenib, bosutinib, gefitinib, axitinib;

afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib,enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib,midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib,radotinib, rigosertib, tipifamib, tivantinib, tivozanib, trametinib,pimasertib, brivanib alaninate, cediranib, apatinib⁴, cabozantinibS-malate^(1,3), ibrutinib^(1,3), icotinib⁴, buparlisib², cipatinib⁴,cobimetinib^(1,3), idelalisib^(1,3), fedratinib¹, XL-647⁴;

Photosensitizers

such as methoxsalen³;

porfimer sodium, talaporfin, temoporfin;

Antibodies

such as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab,denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab,trastuzumab, bevacizumab, pertuzumab^(2,3);

catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab,necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab,ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab,zanolimumab, matuzumab, dalotuzumab^(1,2,3), onartuzumabi-^(1,3),racotumomab¹, tabalumabi^(1,3), EMD-525797⁴, avelumab, nivolumab^(1,3);

Cytokines

such as aldesleukin, interferon alfa², interferon alfa2a³, interferonalfa2b^(2,3); celmoleukin, tasonermin, teceleukin, oprelvekin^(1,3),recombinant interferon beta-1a⁴;

Drug Conjugates

such as denileukin diftitox, ibritumomab tiuxetan, iobenguane I123,prednimustine, trastuzumab emtansine, estramustine, gemtuzumab,ozogamicin, aflibercept;

cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomabestafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab^(1,3),vintafolide^(1,3);

Vaccines

such as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴, rindopepimut³,troVax⁴, MGN-1601⁴, MGN-1703⁴;

Miscellaneous

alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid,imiquimod, lenalidomide, lentinan, metirosine, mifamurtide, pamidronicacid, pegaspargase, pentostatin, sipuleucel³, sizofiran, tamibarotene,temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid,vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib,idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat,peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus,tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat,trabedersen, ubenimex, valspodar, gendicine⁴, picibanil⁴, reolysin⁴,retaspimycin hydrochloride^(1,3), trebananib^(2,3), virulizin⁴,carfilzomib^(1,3), endostatin⁴, immucothel⁴, belinostat³, MGN-1703⁴;

PARP Inhibitors

Olaparib, Veliparib.

¹ Prop. INN (Proposed International Nonproprietary Name)

² Rec. INN (Recommended International Nonproprietary Names)

³ USAN (United States Adopted Name)

⁴ no INN.

The following abbreviations refer respectively to the definitions below:

aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz(Megahertz), min (minute), mm (millimeter), mmol (millimole), mM(millimolar), m.p. (melting point), eq (equivalent), mL (milliliter), μL(microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl₃ (deuteratedchloroform), CD₃OD (deuterated methanol), c-hex (cyclohexane), DCC(dicyclohexyl carbodiimide), DCM (dichloromethane), DIC (diisopropylcarbodiimide), DIEA (diisopropylethyl-amine), DMF (dimethylformamide),DMSO (dimethylsulfoxide), DMSO-d₆ (deuterated dimethylsulfoxide), EDC(1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electrosprayionization), EtOAc (ethyl acetate), Et₂O (diethyl ether), EtOH(ethanol), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluorophosphate), HPLC (High Performance Liquid Chromatography),i-PrOH (2-propanol), K₂CO₃ (potassium carbonate), LC (LiquidChromatography), MeOH (methanol), MgSO₄ (magnesium sulfate), MS (massspectrometry), MTBE (methyl tert-butyl ether), NaHCO₃ (sodiumbicarbonate), NaBH₄ (sodium borohydride), NMM (N-methyl morpholine), NMR(Nuclear Magnetic Resonance), PE (petroleum ether) PyBOP(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate), RT (room temperature), Rt (retention time), SPE(solid phase extraction), TBTU(2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF(tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet), WL(wavelength).

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with EtOAcor DCM, the phases are separated, the organic phase is dried over sodiumsulfate and evaporated, and the residue is purified by chromatography onsilica gel and/or by crystallisation. Rf values on silica gel; eluent:EtOAc/MeOH 9:1.

¹H NMR was recorded on Bruker DPX-300, DRX-400, AVII-400 or on a 500 MHzspectrometer, using residual signal of deuterated solvent as internalreference. Chemical shifts (δ) are reported in ppm relative to theresidual solvent signal (δ=2.49 ppm for ¹H NMR in DMSO-d₆). ¹H NMR dataare reported as follows: chemical shift (multiplicity, couplingconstants, and number of hydrogens). Multiplicity is abbreviated asfollows: s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

Analytical Methods

LCMS

Method A

Column: Chromolith® SpeedROD RP18e 50-4.6

Mobile phase: A=water+0.05% HCOOH, B=ACN+0.04% HCOOH

Gradient: start 4% B, after 2.8 min 100% B, stop after 3.3 min

Flow: 2.4 ml/min

Wave length: 220 nm

Method B

Column: Shim-pack XR-ODS, 3.0*50 mm, 2.2 μm

Mobile phase: A: Water/0.05% TFA, B: ACN/0.05% TFA

Gradient: 5% B to 100% B in 2.0 min, hold 0.5 min

Flow: 1.2 mL/min

Wave length: 254 nm

Method C

Column: Kinetex EVO C18, 3.0×50 mm, 2.6 μm

Mobile phase: A: water with 0.04% NH₄OH, B: ACN

Gradient: 10% B to 95% B in 2.1 min, hold 0.6 min

Flow: 1.2 mL/min

Wave length: 254 nm

Method D

Column: CORTECS C18+, 2.1×50 mm, 2.7 μm

Mobile phase: A: water with 0.1% FA, B: ACN with 0.1% FA

Gradient: 10% B to 100% B till min 2.0, hold till min 2.6 min, 100% B to10% B till min 2.7, stop after 2.90

Flow: 1.0 mL/min

Wave length: 254 nm

Method E

Column: CORTECS C18+, 2.1×50 mm, 2.7 μm

Mobile phase: A: water with 0.1% FA, B: ACN with 0.1% FA

Gradient: 10% B to 100% B till min 3.0, hold till min 4.7 min, 100% B to10% B till min 4.8, stop after min 5

Flow: 1.0 mL/min

Wave length: 254 nm

HPLC

Method A

Column: Chromolith® SpeedROD RP18e 50-4.6

Mobile phase: A=Water+0.01% TFA, B=ACN+0.01% TFA

Gradient: start 10% B, after 3.5 min 100% B, after 4.8 min 10% B, stopafter 5.5 min

Flow: 2.75 mL/min

Wave length: 220 nm

Method B

Column: Atlantis T3, 150×4.6 mm

Mobile phase: A=Water+0.05% TFA, B=ACN+0.05% TFA

Gradient: start 5% B, after 8 min 95% B, after 10.2 min 5% B, stop after12 min

Flow: 1.5 mL/min

Wave length: 254 nm

Method C

Column: Ascentis Express C18 2.7 μm, 100×4.6 mm

Mobile phase: A=Water+0.05% TFA, B=ACN+0.05% TFA

Gradient: start 5% B, after 8 min 95% B, after 10.2 min 5% B, stop after12 min

Flow: 1.5 mL/min

Wave length: 254 nm

Method D

Column: XSELECT HSS T3 100×4.6 mm

Mobile phase: A=Water+0.05% TFA, B=ACN+0.05% TFA

Gradient: start 5% B, after 8 min 95% B, after 10.2 min 5% B, stop after12 min

Flow: 1.2 mL/min

Wave length: 254 nm

Method E

Column: Atlantis HILIC Silica 3 μm 100×4.6 mm

Mobile phase: A=Water+0.05% TFA, B=ACN+0.05% TFA

Gradient: start 5% B, after 8 min 95% B, after 10.2 min 5% B, stop after12 min

Flow: 1.2 mL/min

Wave length: 254 nm

Analytical Chiral Separation

Method A

HPLC

Column: Lux Amylose-2

Mobile phase: n-Heptan: i-PrOH (20:80)

Wave length: 254 nm

Flow: 1 mL/min

Method B

SFC

Column: Lux Amylose-1

Mobile phase: CO₂: i-PrOH+0.5% DEA (88:12)

Wave length: 220 nm

Flow: 5 mL/min

Method C

Method: SFC

Column: ChiralPak AS-H

Mobile phase: CO₂: i-PrOH+0.5% DEA (85:15)

Wave length: 220 nm

Flow: 5 mL/min

Method D

Method: HPLC

Column: ChiralPak IA-3

Mobile phase: Hex(0.1% DEA)/EtOH=1:1

Wave length: 254 nm

Flow: 1.0 mL/min

Method E

Method: HPLC

Column: ChiralPak IA-3

Mobile phase: Hex(0.1% DEA)/EtOH=4:1

Wave length: 254 nm

Flow: 1.0 mL/min

Method F

Method: HPLC

Column: ChiralPak IA-3

Mobile phase: Hex(0.1% DEA)/EtOH=7:3

Wave length: 254 nm

Flow: 1.0 mL/min

Method G

Method: SFC

Column: ChiralPak IC, 3*100 mm, 3 μm

Co-Solvent: MeOH+0.1% DEA

Wave length: 220 nm

Flow: 2 mL/min

Preparative Chiral Separation

Method A

HPLC

column: Lux Amylose-2

Mobile phase: n-Heptan: i-PrOH (20:80)

wave length: 254 nm

flow: 20 ml/min

Biological Activity

Alphascreen Protein Protein Interaction Assay:

For the assessment of functional disruption of the interaction of thePAS B domains of HIF-2α and HIF-1β an AlphaScreen assay was set-up. Theassay was performed in 384 well light gray Perkin Elmer microtiterplates in a total volume of 7 μl. Human rec His6Gb1-TEV-GEFKGL-HIF2α(240-350aa)-G (fc 143 nM) and human rec ARNT His6Gb1-TEV-GEFKGL-ARNT(356-470aa)-FLAG-E362R (fc 143 nM) were incubated with the compound (fc1 nM to 30 μM) of interest in 20 mM Hepes, 150 mM NaCl, 0.05% Tween 20,2 mM DTT, 0.1% (w/v) BSA, 0.3% DMSO, pH 7.5 for 15 min at 23° C. Thedetection of the protein protein interaction was performed by addingAlphaLISA® Anti-FLAG Acceptor beads (fc 20 μg/ml) and AlphaScreen®Nickel Chelate Donor beads (fc 9 μg/ml) (both Perkin Elmer) and thereaction was incubated for 240 min at 23° C. in the dark. If donor andacceptor beads get in close proximity to each other caused byinteraction of HIF2alpha PAS B with HIF-1ß PAS B domain it results in aluminescence signal at 615 nm after excitation at 680 nm. The PPIdisruption activity of a compound was calculated directly from the lossin Alphascreen signal. The AlphaScreen signal was measured with anEnvision multimode reader (Perkin Elmer LAS Germany GmbH). The controlvalue used was the inhibitor-free reaction. The pharmacological zerovalue used was determined in the absence of HIF-11. The inhibitoryvalues (IC50) were calculated using Assay analyser from GeneData.

The compounds inhibit HIF-2α in the assay with an IC₅₀ of A<50 nM,50≤B≤1000 nM, and C>1000 nM as shown in the following table:

Example AlphaScreen 25a C 26a A 27a C 28a C 29a B 30a A 13a A 31a B 32aA 33a A 34a A 36a C 23a A 37a C 38a B 39a C 40a C 41a A 42a A 43a C 44aA 35a C 45a A 46a C 47a C 48a C 49a C 50a C 51a C 54a C 55a A 56a B 57aC 58a C 59a C 61a B 62a B 63a A 64a A 65a C 66a C 67a A 68a B

ITC

ITC measurements were performed with a VP-ITC microcalorimeter fromMicroCal/Malvern (UK). For all titration experiments the protein and therespective compounds were formulated in 30 mM HEPES buffer pH 7.5, 150mM NaCl and 5 mM ß-mercaptoethanol. The protein, HIF2a (240-350)-G, wasprepared by recombinant overexpression and multistep chromatographypurification. Compounds were used from concentrated DMSO stocksolutions. The final protein concentration in the injection syringe was100 μM. Ligand stock solutions of 10 mM in DMSO were diluted to 10 μMconcentrations with buffer and loaded into the sample cell. All bufferswere adjusted to a final concentration of 1% (v/v) DMSO. Both, thetitrate and titrant solutions were degassed prior to loading thecalorimeter cell and injection syringe. ITC titrations were conducted ata constant temperature of 303 K. ITC data analysis was performed usingthe Origin 7 (OriginLab Cooperation Northampton, USA)-based calorimetrycustomization supplied as standard instrument software byMicroCal/Malvern (UK). The integrated heat data were fit with a one-sitebinding model to determine the apparent values for affinity, enthalpyand stoichiometry of binding.

The compounds bind HIF-2α in the assay with an K_(D) of A<50 nM,50≤B≤1000 nM, and C>1000 nM as shown in the following table:

Example ITC 25a C 26a B 27a C 28a C 29a B 30a B 13a B 31a C 32a B 33a B34a B 23a B 37a C 38a B 41a B 42a B 43a C 44a B 63a B 64a B 55a B 45a A

Cellular Mechanistic Assay: 786-O HRE-luc2P Reporter Assay

This reporter assay was designed to monitor binding of the HIF2α-HIF1βcomplex to specific DNA fragment called hypoxia response element (HRE)in physiologically relevant cell line. 786-O HRE-luc2P cells werederived from 786-O human renal cell adenocarcinoma cell line by stableintegration of a HRE Luc reporter construct (pGL4.42 [luc2P/HRE/Hygro]Vector, Promega, cat no. E4001) driving the expression of luciferaseunder the control of HRE sequence. HRE is present in promoters ofvarious genes regulated by hypoxia inducible factors. 786-O cellsexpress only HIF2α. As a result, this reporter assay allows monitoringof HIF2α-HIF1β activity by determining the activity of producedluciferase. Cell culture is performed in RPMI media supplemented with10% FBS, Sodium Pyruvate, Penicillin/Streptomycin, Glutamine, 200 μg/mlHygromycin Gold.

The assay was performed in 384 well white, opaque microtiterplate withtransparent bottom (Greiner Bio-one, Frickenhausen). 786-O HRE-luc2Pcells were resuspended at 4×104 cells/ml in fresh, pre-warmed medium(RPMI, 10% FBS, SP, P/S, Q) w/o hygromycin. 50 μl of cell suspension(2000 cells) per well were dispensed in microtiter plates and incubatedover night at 37° C. in a 5% CO₂ incubator. Compounds were added withLabcyte Echo dispenser (fc 0.2% DMSO, 9 concentrations dilution rawstarting at 10 μM). Plates were incubated for 48 h at 37° C. in a 5% CO₂incubator. After this 45 μl of pre-warmed ONE-Glo™ EX Reagent were addedper well. Plates were placed on an orbital shaker at 1200 rpm for 3minutes. Plates were sealed and luminescence was measured a Tecan Spark20M microplate reader (end-point measurement with 0.1 second readingtime). Values were normalized to DMSO ctrl and wells without cells (onlymedium ctrl). Decrease in luminescence directly correlates withinhibition of HIF2α activity. IC50 values and % effect values werecalculated by GraphPad Prism.

The compounds inhibit HIF-2a in the assay with an IC₅₀ of A<50 nM,50≤B≤1000 nM, and C>1000 nM as shown in the following table:

HRE-luc2P Example reporter assay 26a C 30a C 13a B 31a C 32a C 33a C 34aB 36a C 23a C 37a C 38a C 45a C 46a C 47a C 48a C 54a C 55a C 56a C 61aC 62a C 63a C 64a C

Synthesis

General Procedure A

Synthesis of 3-(2,5-dichlorothiophen-3-yl)propanoic Acid (2)

To 3-(thiophen-3-yl)propanoic acid (6.00 g, 36.49 mmol, 1.00 equiv, 95%)in a 250 mL round-bottom flask was added toluene (70 mL) and SO₂Cl₂(11.92 g, 83.90 mmol, 2.30 equiv, 95%). The resulting solution wasstirred at 69° C. for 4 h. The reaction was then quenched by theaddition of 100 mL of water/ice and extracted with 4×100 mL of EtOAc.The combined organic layer was dried over sodium sulfate, filtered andthe solvent evaporated. The residue was purified via columnchromatography eluting with 0-8% EtOAc in PE to afford 8.89 g of3-(2,5-dichlorothiophen-3-yl)propanoic acid as a colorless solid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 7.07 (s, 1H), 2.75-2.70 (m,2H), 2.54-2.48 (m, 2H); LC-MS (method D): [M−H]⁻=222.75, Rt=0.89 min.

Synthesis of 3-(2,5-dichlorothiophen-3-yl)propanoyl Chloride (3)

To 3-(2,5-dichlorothiophen-3-yl)propanoic acid (8.89 g, 36.89 mmol, 1.00equiv, 93.4%) in a 250 mL round-bottom flask purged with nitrogen wasadded thionyl chloride (80.00 mL, 1.05 mol, 28.40 equiv, 95%). Theresulting solution was stirred at 25° C. for 3 h. The mixture was thenconcentrated under reduced pressure to afford 8.32 g of3-(2,5-dichlorothiophen-3-yl)propanoyl chloride as orange oil which wasused without further purification.

Synthesis of 1,3-dichloro-5H,6H-cyclopenta[c]thiophen-4-one (4)

3-(2,5-dichlorothiophen-3-yl)propanoyl chloride (8.32 g, 32.04 mmol,1.00 equiv, 93.8%) was dissolved in DCM (80 mL) in a 500 mL round-bottomflask purged with nitrogen and the solution was cooled to 0-5° C. AlCl₃(35.98 g, 256.3 mmol, 8.00 equiv, 95%) was added slowly. The resultingmixture was stirred at 25° C. for 5 h. It was then poured into 1 L ofwater/ice and extracted with 3×300 mL of EtOAc. The combined organiclayer was dried over sodium sulfate and the solvent evaporated. Theresidue was purified via column chromatograph eluting with EtOAc (0-10%)in PE to afford 4.02 g 1,3-dichloro-5H,6H-cyclopenta[c]thiophen-4-one asa light yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 3.01-2.95 (m, 2H), 2.87-2.81 (m, 2H); LC-MS(Method D): [M+H]⁺=206.80, Rt=0.95 min.

Synthesis of 1,3-dichloro-5-fluoro-5H,6H-cyclopenta[c]thiophen-4-one (5)

To 1,3-dichloro-5H,6H-cyclopenta[c]thiophen-4-one (4.10 g, 18.8 mmol,1.00 equiv, 95%) in a 250 mL round-bottom flask was added1,3-dichloro-4H,5H,6H-cyclopenta[c]thiophen-4-one (4.10 g, 18.8 mmol,1.00 equiv, 95%), selectfluor (10.52 g, 28.2 mmol, 1.50 equiv, 95%),MeOH (50 mL), and concentrated sulfuric acid (564.7 mg, 5.64 mmol, 0.30equiv, 98%). The reaction was stirred for 48 h at 69° C. After fullconvertion of the starting material, water (30 mL) was added and theresulting mixture was stirred for 4 h at 69° C. It was then extractedwith 3×100 mL of EtOAc and the combined organic layer was dried oversodium sulfate, filtered and concentrated. The residue was purified viacolumn chromatography eluting with EtOAc/PE (1:10) to afford 4.5 g of1,3-dichloro-5-fluoro-5H,6H-cyclopenta[c]thiophen-4-one as a colorlesssolid.

LC-MS (Method D): [M+H]⁺=224.75, Rt=0.94 min.

Synthesis oftert-butyl({1,3-dichloro-5-fluoro-4H-cyclopenta[c]thiophen-6-yl}oxy)dimethylsilane(6)

To a 250 mL round-bottom flask purged with nitrogen was added1,3-dichloro-5-fluoro-5H,6H-cyclopenta[c]thiophen-4-one (4.30 g, 16.2mmol, 1.00 equiv, 85%), DCM (60 mL), TEA (11.9 mL, 81.2 mmol, 5.00equiv, 95%), and TBSOTf (5.42 g, 19.5 mmol, 1.20 equiv, 95%). Theresulting solution was stirred for 3 h at 0° C. and then concentratedunder vacuum. The residue was directly purified via columnchromatography eluting with EtOAc in PE (1:100) to afford 6.0 g oftert-butyl({1,3-dichloro-5-fluoro-4H-cyclopenta[c]thiophen-6-yl}oxy)dimethylsilaneas a colorless solid.

¹H NMR (300 MHz, CDCl₃): δ 3.24 (d, J=3.1 Hz, 2H), 1.03 (s, 9H), 0.27(d, J=1.7 Hz, 6H).

Synthesis of1,3-dichloro-5,5-difluoro-4H,5H,6H-cyclopenta[c]thiophen-4-one (7)

To a 500 mL round-bottom flask purged with nitrogen was addedtert-butyl({1,3-dichloro-5-fluoro-4H-cyclopenta[c]thiophen-6-yl}oxy)dimethylsilane(3.00 g, 7.25 mmol, 1.00 equiv, 82%), selectfluor (4.06 g, 10.9 mmol,1.50 equiv, 95%), and ACN (100 mL). The reaction mixture was stirred for3 h at 0° C. The solids were filtered off and the filtrate concentratedunder vacuum. The residue was then purified via column chromatographyeluting with EtOAc/PE (1:20) to afford 1.8 g of1,3-dichloro-5,5-difluoro-4H,5H,6H-cyclopenta[c]thiophen-4-one as ayellow solid.

¹H NMR (300 MHz, CDCl₃): δ 3.31 (t, J=12.9 Hz, 2H).

Synthesis of1-chloro-5,5-difluoro-3-(methylsulfanyl)-4H,5H,6H-cyclopenta[c]thiophen-4-one(8)

To a 100 mL round-bottom flask purged with nitrogen was added1,3-dichloro-5,5-difluoro-4H,5H,6H-cyclopenta[c]thiophen-4-one (900 mg,3.33 mmol, 1.00 equiv, 90%), (methylsulfanyl)sodium (285 mg, 3.86 mmol,1.16 equiv, 95%), and THF (30 mL). The reaction mixture was stirred for3 h at RT. It was then quenched by the addition of 30 mL of water/ice.The resulting mixture was extracted with 3×30 mL of EtOAc. The combinedorganic layer was dried over sodium sulfate and concentrated undervacuum. The residue was purified via column chromatography eluting withEtOAc/PE (1:30) to afford 450 mg of1-chloro-5,5-difluoro-3-(methylsulfanyl)-4H,5H,6H-cyclopenta[c]thiophen-4-oneas a yellow solid.

LC-MS (Method D): [M+H]⁺=254.80, Rt=1.05 min.

Synthesis of1-chloro-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one(9)

To a stirred solution of1-chloro-5,5-difluoro-3-(methylsulfanyl)-4H,5H,6H-cyclopenta[c]thiophen-4-one(1.17 g, 4.36 mmol, 1 equiv, 95%) in MeOH was added oxone (6.2 g, 35.0mmol, 8.03 equiv, 95%) in portions at RT under nitrogen atmosphere. Theresulting mixture was stirred under nitrogen atmosphere overnight at RT.The resulting mixture was filtered and the filter cake was washed withEtOAc (4×20 mL). The filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography elutingwith PE/EtOAc (5:1) to afford 1.1 g of1-chloro-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-oneas colorless solid.

¹H NMR (300 MHz, CDCl₃): δ 3.51-3.35 (m, 5H).

Synthesis of1-chloro-5,5-difluoro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′-[1,3]dioxolane](10)

To1-chloro-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one(2.5 g, 7.85 mmol, 1 equiv, 90%) in a 100 mL round-bottom flask wasadded DMF (30 mL), K₂CO₃ (2.4 g, 16.5 mmol, 2.10 equiv, 95%), and2-bromoethan-1-ol (2.1 g, 15.96 mmol, 2.03 equiv, 95%) at RT. Theresulting mixture was stirred for 2 h at RT. It was then diluted with100 mL EtOAc and washed with water (3×100 mL). The organic phase wasdried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified via column chromatography eluting with (PE/EtOAc3:1) to afford 2.5 g of1-chloro-5,5-difluoro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′-[1,3]dioxolane]as colorless solid. ¹H NMR (300 MHz, CDCl₃): δ 4.49-4.44 (m, 2H),4.29-4.25 (m, 2H), 3.30-3.19 (m, 5H); LC-MS (Method D): [M+H]⁺=330.95,Rt=0.87 min.

Synthesis of1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′-[1,3]dioxolane](11)

To1-chloro-5,5-difluoro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′-[1,3]dioxolane](300 mg, 1.36 mol, 1 equiv, 90%) in a 20 mL sealed tube at RT was added(3-chloro-5-fluoro-phenyl)boronic acid (173 mg, 1.71 mol, 1.26 equiv,95%), Pd(PPh₃)₄ (104 mg, 0.14 mmol, 0.11 equiv, 95%), Na₂CO₃ (144 mg,2.15 mmol, 1.58 equiv, 95%), dioxane (8 mL) and H₂O (1 mL). Theresulting mixture was subjected to three cycles of vacuum/nitrogen flushand stirred for 1 h at 80° C. under nitrogen atmosphere. The resultingmixture was concentrated under vacuum. The residue was purified byPrep-TLC with 3:1 PE/EtOAc to afford 150 mg of1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′-[1,3]dioxolane]as a colorless solid.

LC-MS (Method D): [M+H]⁺=424.85, Rt=1.16 min.

Synthesis of1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one(12)

To1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2′-[1,3]dioxolane](150 mg, 1.27 mmol, 1 equiv, 90%) in a 50 mL round-bottom flask wasadded DCM (6 mL), HClO₄ (2 mL, 50 mmol, 39 equiv, 95%). The reactionmixture was stirred for 2 h at RT. It was then diluted with 50 mL ofDCM. The organic phase was washed with 50 mL of aqueous NaHCO₃, driedover sodium sulfate, and concentrated under vacuum to afford 120 mg of1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-oneas a yellow solid.

LC-MS (Method D): [M+H]⁺=380.85, Rt=1.0 min.

Synthesis of1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol(13)

To a stirred solution of1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one(120 mg, 0.19 mmol, 1 equiv, 60%) in THF (5 mL) was added NaBH₄ (30 mg,0.75 mmol, 4 equiv, 95%) in portions at RT under nitrogen atmosphere.The resulting mixture was stirred for 2 h at RT and quenched by theaddition of water (10 mL) at RT. The resulting mixture was extractedwith EtOAc (3×10 mL). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudeproduct (100 mg) was purified by Prep-HPLC under the followingconditions (Prep-HPLC-015): Column, XBridge Shield RP18 OBD Column,30*150 mm, 5 um; mobile phase, water (10 mmol/L NH₄HCO₃+0.1% NH₃.H₂O)and ACN (40% Phase B up to 65% in 8 min); Detector: UV. This resulted in1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol(15 mg, 21%) as a colorless solid.

LC-MS (Method D): [M+Na]⁺=405.10, Rt=1.54 min.

Chiral Resolution of1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol(13)

300 mg of1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol(13) were separated by Chiral-Prep-HPLC under the following condition:Column: CHIRALPAK IA, 2.12*15 cm, 5 μm; Mobile Phase A: Hex, MobilePhase B: EtOH; Flow rate: 20 mL/min; Gradient: 50 B to 50 B in 7 min;220/254 nm; Rt1: 3.3 min; Rt2: 4.9 min. This resulted in 143.9 mg of(4S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-olas a white solid with a melting point of 130-132° C.

13a: ¹H NMR (400 MHz, CD₃OD): δ=7.48 (s, 1H), 7.41-7.26 (m, 2H), 5.18(dd, J=11.5, 3.2 Hz, 1H), 3.69-3.43 (m, 2H), 3.38 (s, 3H); LC-MS (MethodD): Rt=1.38 min, [M−HF—H]⁻=360.7; HPLC (method D): purity >99%, Rt 6.79min; chiral HPLC (method D): >99% ee, Rt 1.21 min, (13b: >99% ee,Rt=1.94 min).

General Procedure B

Synthesis of ethyl3-(methylsulfanyl-4-oxo-4,5,6,7-tetrahydro-2-benzothiophone-1-carboxylate(14)

In a 250 mL three-neck round-bottom flask equipped with stir bar,thermometer and septum, 1,3-cyclohexanedione (10 g, 89.19 mmol) wasdissolved in DMF (75 mL) and potassium carbonate (36.98 g, 267.5 mmol)was added. The mixture was stirred at RT for 15 min. Carbon disulfide(6.44 mL, 107.02 mmol) was added and the mixture was stirred for 20 minat RT. Subsequently, a solution of ethyl chloroacetate (9.50 mL, 89.19mmol) in DMF (85 mL) was added dropwise over a period of 3 h at 20-25°C. and the resulting red-brown mixture was stirred at RT for 30 min. Themixture was cooled to 0-5° C. and iodomethane (5.6 mL, 89.19 mmol) wasadded dropwise over a period of 15 min. The red-brown mixture wasstirred at 0-5° C. for additional 60 min. The mixture was slowly warmedto RT and stirred overnight. The dark brown reaction mixture was pouredinto 1.6 L of ice/water then extracted with 3×DCM. The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andevaporated to dryness. The brown oily residue was purified in two runsby flash chromatography. Yield: 12.86 g red-brown solid.

HPLC (method A): purity 98.0%, Rt=2.77 min; LC-MS (method A):[M+H]⁺=271.0, Rt=2.34 min.

Synthesis of3-(methylsulfanyl)-4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylicAcid (15)

In a 100 mL round-bottom flask equipped with stir bar and condenserethyl3-(methylsulfanyl)-4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylate(25.88 g, 86.05 mmol) was suspended in EtOH (65 mL) and aqueous sodiumhydroxide solution NaOH (2 M, 64.54 mL, 129.08 mmol) was added. Themixture was heated to 70° C. and stirred for 45 min. A brown solutionwas formed. The mixture was cooled to RT and acidified with HCl (2 M,64.54 mL, 129.08 mmol) to pH 3. A light yellow precipitate was formed.It was filtered and washed with water, a small amount of ACN and MTBE.The filter cake was dried under vacuum at 50° C. overnight. Yield: 22.5g light yellow solid. HPLC (method A): purity 98.1%, Rt=2.05 min; LC-MS(method A): [M+H]⁺=242.9, Rt=1.73 min.

Synthesis of 3-(methylsulfanyl)-4,5,6,7-tetrahydro-2-benzothiophen-4-one(16)

In a 250 mL round-bottom flask equipped with stir bar and condenser3-(methylsulfanyl)-4-oxo-4,5,6,7-tetrahydro-2-benzothiophene-1-carboxylicacid (22.5 g, 91.09 mmol) and copper powder (2.2 g, 34.61 mmol) wereplaced in a flask and suspended in quinoline (60 mL). The mixture washeated to reflux (bath temp. 245° C.) and stirred for 45 min. The darkbrown reaction mixture was cooled to RT, quenched with HCl (2 M, 800 mL)and stirred for 10 min. The mixture was extracted with 3×120 mL DCM. Thecombined organic layers were washed with water and saturated NaHCO₃,dried over sodium sulfate, filtered and the solvent evaporated. The oilyresidue was purified by flash chromatography. Yield: 16.9 g brown oil.

HPLC (method A): purity 98.0%, Rt=2.34 min; LC-MS (method A):[M+H]⁺=199.0, Rt=2.036 min.

Synthesis of1-bromo-3-(methylsulfanyl)-4,5,6,7-tetrahydro-2-benzothiophen-4-one (17)

In a 250 mL two-neck round-bottom flask equipped with stir bar,thermometer and septum,3-(methylsulfanyl)-4,5,6,7-tetrahydro-2-benzothiophen-4-one (16.9 g,83.52 mmol) was dissolved in DCM (175 mL) and cooled to 0-5° C.N-bromosuccinimide (16.351 g, 91.87 mmol) was added and the mixture wasstirred at 0-5° C. for 1 h. The yellow cloudy solution was diluted with50 mL DCM, washed twice with water and once with saturated NaHCO₃solution, dried with sodium sulfate, filtered and the solventevaporated. The solid residue was suspended in MBTE, filtered, washedwith a small amount of MBTE and dried. Yield: 20 g grey solid.

HPLC (method A): purity >99%, Rt=2.89 min; LC-MS (method A):[M+H]⁺=276.8, Rt=2.46 min.

Synthesis of1-bromo-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one (18)

In a 100 mL round-bottom flask equipped with stir bar and septum,1-bromo-3-(methylsulfanyl)-4,5,6,7-tetrahydro-2-benzothiophen-4-one(6.54 g, 23.5 mmol), sodium metaperiodate (15.08 g, 70.5 mmol) andruthenium(III) chlorid (731.14 mg; 3.525 mmol) were suspended in ACN (5mL), DCM (30 mL) and water (20 mL). The mixture was stirred at RT for 1h. The reaction mixture was filtered over kieselguhr and the filter cakewas washed three times with DCM. The filtrate was washed with water andsaturated NaHCO₃ solution, dried with sodium sulfate, filtered and thesolvent evaporated. The solid residue was purified by flashchromatography. Yield: 6.42 g light yellow solid.

HPLC (method A): purity 97.5%, Rt=2.28 min; LC-MS (method A):[M+H]⁺=308.9, Rt=1.96 min.

Synthesis of1-bromo-5-fluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one(19)

In a 250 ml round-bottom flask equipped with stir bar, condenser andseptum,1-bromo-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one (6.42g, 20.76 mmol) was dissolved in MeOH (75 mL). Selectfluor (15.49 g, 41.5mmol) and water (25 mL) were added under argon followed by sulfuric acid(98%, 553 μL, 10.38 mmol). The mixture was heated to 66° C. and stirredovernight. The starting material was not fully converted and additionalMeOH (30 mL), water (15 ml) and sulfuric acid (98%, 0.277 mL, 5.19 mmol)were added. The yellow solution was stirred at 66° C. for 24 h. Thereaction mixture was cooled to RT and evaporated till only the aqueousphase remained. The aq. residue was diluted with 50 mL of water andextracted 3 times with EtOAc. The combined organic layer was washed withbrine, dried over sodium sulfate, filtered and the solvent evaporated.The residue was purified via flash chromatography yielding a yellowsolid. Yield: 4.77 g.

HPLC (method A): purity 98.7%, Rt=2.21 min; LC-MS (method A):[M+H]⁺=326.8, Rt=1.92 min.

Synthesis of[(1-bromo-5-fluoro-3-methanesulfonyl-6,7-dihydro-2-benzothiophen-4-yl)oxy](tert-butyl)dimethylsilane(20)

In a 50 mL round-bottom flask equipped with stir bar and septum1-bromo-5-fluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one(1.75 g, 5.35 mmol) was dissolved in DCM (30 mL) and TEA (3.74 mL, 26.74mmol) was added under argon. tert-butyldimethylsilyltrifluoromethanesulfonate (1.88 mL, 8.02 mmol) was than slowly added tothe solution. The brown solution was stirred at RT overnight. Since thestarting material was not fully converted 1,2-dichloroethane (8 mL) andadditional tert-butyldimethylsilyl trifluoromethanesulfonate (1.25 mL,5.35 mmol) were added, the mixture was heated to reflux and stirred for24 h. The reaction mixture was diluted with 50 mL DCM, washed withwater, 5% citric acid solution and brine, dried over sodium sulfate,filtered and the solvent evaporated. The brown oily residue was purifiedvia flash chromatography yielding a yellow solid. Yield: 1.96 g.

HPLC (method A): purity >99%, Rt=3.66 min; LC-MS (method A):[M+H]⁺=440.8, Rt=3.05 min.

Synthesis of1-bromo-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one(21)

In 100 mL round-bottom flask equipped with stir bar and septum,[(1-bromo-5-fluoro-3-methanesulfonyl-6,7-dihydro-2-benzothiophen-4-yl)oxy](tert-butyl)dimethylsilane(1.96 g, 4.44 mmol) was suspended in ACN (35 mL). The mixture was cooledto 0-5° C. and selectfluor (2.05 g, 5.77 mmol) was then added underargon. The mixture was stirred at 0-5° C. for 2.5 h and diluted with 100mL water and extracted 3 times with EtOAc. The combined organic layerswere washed with NaHCO₃ solution and brine, dried over sodium sulfate,filtered and the solvent evaporated. The solid residue was purified viaflash chromatography yielding a colorless solid. Yield: 1.28 g.

HPLC (method A): purity 92.1%, Rt=2.49 min; LC-MS (method A):[M+H]⁺=344.7; Rt=2.14 min.

Synthesis of1-bromo-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(22)

In a 5 mL glass vial equipped with stir bar and septum,1-bromo-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one(0.91 g, 2.51 mmol) was suspended in MeOH (14 mL) and NaBH₄ (0.19 g,5.03 mmol) was then added in portions over a period of 15 min (gasevolution, temperature increased to 30° C.). The mixture was stirred atRT for additional 5 min. The reaction was quenched with 1 mL saturatedNH₄Cl solution, stirred for 5 min, then diluted with 30 mL of water andextracted twice with EtOAc. The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and the solvent evaporated.Yield: 5.52 g grey-brown solid.

HPLC (method A): purity 97.9%, Rt=2.53 min, LC-MS (method A):[M−H₂O+H]⁺=328.8, Rt=2.08 min.

Chiral Separation of1-bromo-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol

The preparative separation of the enantiomers was carried out by SFC ona Lux Amylose-1 column with CO₂: i-PrOH+0.5% DEA (85:15) as eluent at 5ml/min flow rate. The collected fraction with product were evaporated todryness. The products were lyophilized overnight and a light yellowsolid was obtained.

22a: LC-MS (method A): [M−H₂O+H]⁺=328.8, Rt: 2.08 min; HPLC (methodA): >99%, Rt=2.53 min; chiral SFC (method C): 98.7% er, Rt=2.2 min(22b: >97.4% ee, Rt=3.61 min).

Synthesis of(S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(23a)

(S)-1-bromo-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(50 mg, 0.113 mmol), 3,5-difluorophenylboronic acid (26.8 mg, 0.170mmol), sodium carbonate (30 mg, 0.283 mmol) anddichlorobis(triphenylphosphine)palladium (4.0 mg, 0.006 mmol) wereplaced in a 5 mL glass vial and suspended in ACN (3 mL) and water (0.5mL). The vial was sealed with a septum and argon was bubbled through thereaction mixture for 2 min. The mixture was heated to 60° C. and stirredfor 1 h. The reaction mixture was cooled to RT, diluted with 30 ml waterand extracted 3 times with EtOAc. The combined organic layers werewashed with brine, dried with sodium sulfate, filtered and evaporated todryness. The oily residue was purified via chromatography and theproduct was lyophilized overnight. Yield: 42.9 mg colorless powder.

¹H NMR (400 MHz, DMSO-d₆): δ=7.42-7.34 (m, 3H), 6.84 (d, J=6.5 Hz, 1H),5.15-5.08 (m, 1H), 3.45 (s, 3H), 3.00-2.94 (m, 2H), 2.47-2.28 (m, 1H),2.25-2.13 (m, 1H); LC-MS (method A): [M−H₂O+H]⁺=362.9, Rt: 2.33 min;HPLC (method A): >99.8%, Rt=2.78 min; chiral SFC (method B): >99% ee,Rt=3.52 min.

General Procedure C

Synthesis of1-(3,5-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one(24)

1-Bromo-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one(197.0 mg, 0.485 mmol), 3,5-difluorophenylboronic acid (114.9 mg, 0.728mmol), sodium carbonate (128.5 mg, 1.213 mmol) andbis(triphenylphosphine)palladium chloride (17.0 mg, 0.024 mmol) wereplaced in a 12 mL glass vial and suspended in ACN (10 mL) and water (1.5mL). The vial was sealed with a septum and argon was bubbled through thereaction mixture for 2 min. The mixture was heated to 60° C. and stirredfor 4 h. The reaction mixture was cooled to RT, diluted with 30 mL waterand extracted 3 times with EtOAc. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and evaporated todryness. The oily residue was purified by flash chromatography and prep.HPLC (Agilent 1260; Waters SunFire C18; 5 μm 30×150 mm column; WL:220/254 nm). A yellow powder was obtained. Yield: 95.1 mg.

HPLC (method A): purity 88.5%, RT=2.89 min; LC-MS (method A):[M+H]⁺=378.9; Rt=2.33 min.

Synthesis of1-(3,5-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(23)

1-(3,5-Difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one(95.1 mg, 0.251 mmol) was placed in a 12 mL glass vial and suspended inMeOH (3 mL). NaBH₄ (16.8 mg, 0,445 mmol) was added and the mixture wasstirred at RT for 5 min. The reaction mixture was quenched with 1 mLsaturated NH₄Cl solution and stirred for 5 min, then diluted with 30 mLEtOAc, washed with water and brine, dried over sodium sulfate, filteredand evaporated to dryness.1-(3,5-Difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-olwas obtained as light yellow solid. Yield: 101 mg.

HPLC (method A): 99.7%, RT=2.80 min; LC-MS (method A): [M−H₂O+H]⁺=362.8,RT=2.327 min.

Chiral Resolution of1-(3,5-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(23)

The preparative separation of the enantiomers was carried out by SFC ona Lux Amylose-1 column with CO₂: i-PrOH+0.5% DEA (88:12) as eluent at 5ml/min flow rate. The collected fraction with product were evaporated todryness. The products were lyophilized overnight and a colorless solidwas obtained.

23a: ¹H NMR (400 MHz, DMSO-d₆): δ=7.42-7.34 (m, 3H), 6.84 (d, J=6.5 Hz,1H), 5.15-5.08 (m, 1H), 3.45 (s, 3H), 3.00-2.94 (m, 2H), 2.47-2.28 (m,1H), 2.25-2.13 (m, 1H); LC-MS (method A): [M−H₂+H]⁺=362.9, Rt: 2.33 min;HPLC (method A): >99.8%, Rt=2.78 min; chiral SFC (method B): >99% ee,Rt=3.52 min (23b: >99% ee, Rt=2.53 min).

Following compounds have been obtained analogously:

(4S)-5,5-difluoro-3-methanesulfonyl-1-phenyl-4H,6H-cyclopenta[c]thiophen-4-ol(25a)

Prepared according to general procedure A; ¹H NMR (300 MHz, CDCl₃):δ=7.62-7.32 (m, 5H), 5.31 (dd, J=11.7, 4.3 Hz, 1H), 3.64-3.33 (m, 3H),3.32 (s, 3H); LC-MS (Method B): Rt=1.63 min, [M+Na]⁺=353.2; HPLC (methodB): purity 99.1%, Rt 5.99 min; chiral HPLC (method D): >99% ee, Rt 1.59min. The (4R)-enantiomer has been obtained analogously.

(4S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol(26a)

Prepared according to general procedure A; ¹H NMR (400 MHz, DMSO-d₆):δ=7.51-7.29 (m, 3H), 6.88 (d, J=6.7 Hz, 1H), 5.21-4.96 (m, 1H),3.88-3.51 (m, 2H), 3.46 (s, 3H); LC-MS (method C): Rt=1.57 min,[M−HF—H]⁻=345.1; HPLC (method C): purity 98.9%, Rt 5.12 min; chiral HPLC(method D): >99% ee, Rt 1.83 min.

The (4R)-enantiomer has been obtained analogously.

(4S-5,5-difluoro-1-(2-fluorophenyl)-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol(27a)

Prepared according to general procedure A; ¹H NMR (300 MHz, DMSO-d₆):δ=7.71 (td, J=7.8, 1.8 Hz, 1H), 7.60-7.53 (m, 1H), 7.49-7.35 (m, 2H),6.84 (d, J=6.9 Hz, 1H), 5.18-5.11 (m, 1H), 3.65-3.39 (m, 5H); LC-MS(method B): Rt=1.58 min, [M+Na]⁺=371.2; HPLC (method D): purity 99.6%,Rt=6.18 min; chiral HPLC (method E): >99% ee, Rt=2.56 min.

The (4R)-enantiomer has been obtained analogously.

(4S-5,5-difluoro-1-(3-fluorophenyl)-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol(28a)

Prepared according to general procedure A; ¹H NMR (400 MHz, DMSO-d₆):δ=7.67-7.42 (m, 3H), 7.31 (tdd, J=8.2, 2.4, 1.2 Hz, 1H), 6.82 (d, J=6.8Hz, 1H), 5.14-5.07 (m, 1H), 3.77-3.49 (m, 2H), 3.44 (s, 3H); LC-MS(method B): Rt=1.61 min, [M+Na]⁺=371.2; HPLC (method D): purity 99.8%,Rt=6.26 min; chiral HPLC (method F): >99% ee, Rt=1.98 min.

The (4R)-enantiomer has been obtained analogously.

(4S-5,5-difluoro-1-(4-fluorophenyl)-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol(29a)

Prepared according to general procedure A; ¹H NMR (400 MHz, DMSO-d₆):δ=7.71 (dd, J=8.8, 5.3 Hz, 2H), 7.36 (t, J=8.8 Hz, 2H), 6.79 (d, J=7.0Hz, 1H), 5.17-5.03 (m, 1H), 3.73-3.46 (m, 2H), 3.43 (s, 3H); LC-MS(method B): Rt=1.60 min, [M+Na]⁺=371.2; HPLC (method D): purity 99.3%,Rt=6.24 min; chiral HPLC (method F): >99% ee, Rt=2.16 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(3,4-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol(30a)

Prepared according to general procedure A; ¹H NMR (400 MHz, CD₃OD):δ=7.58 (ddd, J=11.5, 7.6, 1.8 Hz, 1H), 7.51-7.34 (m, 2H), 5.17 (dd,J=11.5, 3.1 Hz, 1H), 3.65-3.40 (m, 2H), 3.37 (s, 3H); LC-MS (method C):Rt=1.56 min, [M+NH4]⁺=384.1; HPLC (method D): purity 97.3%, Rt=6.204min; chiral HPLC (method F): >99% ee, Rt=1.77 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol(13a)

Prepared according to general procedure A; ¹H NMR (400 MHz, CD₃OD):δ=7.48 (s, 1H), 7.41-7.26 (m, 2H), 5.18 (dd, J=11.5, 3.2 Hz, 1H),3.69-3.43 (m, 2H), 3.38 (s, 3H); LC-MS (Method D): Rt=1.38 min,[M−HF—H]⁻=360.7; HPLC (method D): purity >99%, Rt=6.79 min; chiral HPLC(method D): >99% ee, Rt=1.21 min.

The (4R)-enantiomer has been obtained analogously.

4-[(4S-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,6H-yclopenta[c]thiophen-1-yl]-2-fluorobenzonitrile(31a)

Prepared according to general procedure A; ¹H NMR (300 MHz, CD₃OD, ppm):δ=7.91-7.86 (m, 1H), 7.67-7.61 (m, 2H), 5.19 (dd, J=11.5, 3.1 Hz, 1H),3.72-3.50 (m, 2H), 3.39 (s, 3H); LC-MS (Method D): Rt=2.25 min,[M−HF—H]⁻=351.7; HPLC (method E): purity >99%, Rt=5.98 min; chiral HPLC(method D): >99% ee, Rt=1.66 min.

The (4R)-enantiomer has been obtained analogously.

3-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-1-yl]benzonitrile(32a)

Prepared according to general procedure A; ¹H NMR (400 MHz, DMSO-d₆):δ=8.12 (t, J=1.7 Hz, 1H), 8.02-7.87 (m, 2H), 7.70 (t, J=7.9 Hz, 1H),6.82 (d, J=6.8 Hz, 1H), 5.10 (ddd, J=11.0, 6.6, 3.9 Hz, 1H), 3.89-3.53(m, 2H), 3.45 (s, 3H); LC-MS (Method C): Rt=1.41 min, [M+Na]⁺=378.2;HPLC (method D): purity 98.3%, Rt=5.73 min; chiral HPLC (method D): >99%ee, Rt=1.83 min.

The (4R)-enantiomer has been obtained analogously.

3-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-1-yl]-5-fluorobenzonitrile(33a)

Prepared according to general procedure A; ¹H NMR (400 MHz, CD₃OD):δ=7.84 (t, J=1.5 Hz, 1H), 7.73 (dt, J=9.4, 2.1 Hz, 1H), 7.67 (ddd,J=8.1, 2.4, 1.3 Hz, 1H), 5.19 (dd, J=11.5, 3.2 Hz, 1H), 3.71-3.46 (m,2H), 3.39 (s, 3H); LC-MS (Method D): Rt=1.19 min, [M−HF—H]⁻=351.7; HPLC(method D): purity 99.1%, Rt=5.99 min; chiral HPLC (method D): >99% ee,Rt=1.76 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-3-chloro-5-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-1-yl]benzonitrile(34a)

Prepared according to general procedure A; ¹H NMR (400 MHz, DMSO-d6):δ=8.12 (dt, J=8.5, 1.5 Hz, 2H), 8.03 (t, J=1.8 Hz, 1H), 6.84 (d, J=6.8Hz, 1H), 5.10 (ddd, J=11.2, 6.8, 4.0 Hz, 1H), 3.83-3.56 (m, 3H), 3.46(s, 3H); LC-MS (Method D): Rt=1.28 min, [M−HF—H]⁻=367.6; HPLC (methodD): purity 99.9%, Rt=6.34 min; chiral HPLC (method D): >99% ee, Rt=1.60min.

The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(1-methyl-1H-pyrazol-4-yl)-4H,5H,6H-cyclopenta[c]thiophen-4-ol(35a)

Prepared according to general procedure A; ¹H NMR (300 MHz, DMSO-d6):δ=8.25 (s, 1H), 7.85 (s, 1H), 6.70 (s, 1H), 5.05 (dd, J=11.7, 3.9 Hz,1H), 3.89 (s, 3H), 3.57-3.41 (m, 2H), 3.41 (s, 3H); LC-MS (Method D):Rt=0.85 min, [M+H]⁺=335.0; HPLC (method D): purity 99.0%, Rt=4.5 min;chiral HPLC (method D): 99.8% ee, Rt=1.93 min.

The (4R)-enantiomer has been obtained analogously.

(4R)-3-methanesulfonyl-1-phenyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(36a)

1-Bromo-3-(methylsulfanyl)-4,5,6,7-tetrahydro-2-benzothiophen-4-one (17,500 mg, 1.8 mmol), Phenylboronic acid pinacol ester (455 mg, 2.2 mmol),sodium carbonate (401 mg, 3.8 mmol) andtetrakis(triphenylphosphine)-palladium(0) (41.7 mg, 0.036 mmol) wereplaced in a vial and suspended in THF (5 mL) and water (5 mL). The vialwas sealed with a septum and argon was bubbled through the reactionmixture for 5 min. The mixture was heated to 70° C. and stirred for 16h. The reaction mixture was cooled to room temperature, diluted with 20mL water and extracted 3 times with EtOAc. The combined organic layerswere washed with brine, dried with sodium sulfate, filtered andevaporated to dryness. The oily residue was purified by columnchromatography to afford3-(methylsulfanyl)-1-phenyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one.Yield: 107 mg light yellow solid (HPLC: 97.4%, Rt: 3.11 min; LC-MS:[M+H]⁺=275.9, Rt: 2.63 min).3-(Methylsulfanyl)-1-phenyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one(107 mg, 0.38 mmol), sodium metaperiodate (244 mg, 1.14 mmol) andruthenium(III)chlorid (11.8 mg, 0.057 mmol) were then placed in a vialand suspended in ACN (1.5 mL), carbon tetrachloride (1.5 mL) and water(3 mL). The mixture was stirred at room temperature overnight. Thereaction mixture was filtered over celite and the solids were washed 3×with EtOAc. The filtrate was washed with water, saturated NaHCO₃solution and brine, dried over sodium sulfate, filtered and evaporatedto dryness to obtain3-methanesulfonyl-1-phenyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one.Yield: 114 mg light brown solid (HPLC: 90.6%, Rt: 2.65 min; LC-MS:[M+H]⁺=306.9, Rt: 2.23 min).3-Methanesulfonyl-1-phenyl-4,5,6,7-tetrahydro-2-benzothiophen-4-one(114. mg, 0.337 mmol) was then placed in a vial and dissolved in MeOH (3mL). Sodium borohydride (25.5 mg, 0.674 mmol) was added under argon andthe mixture was stirred at RT for 15 min. The reaction was quenched with2 mL saturated NH₄Cl solution, diluted with 20 mL water and extracted 3×with EtOAc. The combined organic layers were washed with brine, driedover sodium sulfate, filtered and evaporated to dryness. The oilyresidue was purified by column chromatography to obtain3-methanesulfonyl-1-phenyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol.Yield: 92.3 mg colorless solid (HPLC: 99.2, Rt: 2.61 min, LC-MS:[M−H₂O+H]⁺=290.9, Rt: 2.20 min).

The preparative separation of the enantiomers was carried out by SFC ona Lux Amylose-1 column with CO2: i-PrOH+0.5% DEA (80:20) as eluent at 20mL/min flow rate. The collected fraction with product were evaporated todryness. The products were lyophilized overnight and a colorless solidwas obtained.

¹H NMR (500 MHz, DMSO-d6): δ=7.56-7.49 (m, 4H), 7.47-7.43 (m, 1H), 5.39(d, J=5.6 Hz, 1H), 5.20-5.16 (m, 1H), 3.45 (s, 3H), 2.78-2.63 (m, 2H),1.91-1.75 (m, 3H), 1.69-1.63 (m, 1H); LC-MS (method A):[M−H₂O+H]⁺=290.9, Rt=2.19 min; HPLC (method A): purity 97.6%, Rt=2.59min, chiral HPLC (method A): 99.4% er, Rt=9.64 min.

The (4S)-enantiomer has been obtained analogously.

(4S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-6,7-dihydro-4H-2-benzothiophen-4-ol(23a)

Colorless solid prepared according to general procedures A and B; ¹H NMR(400 MHz, DMSO-d₆): δ=7.42-7.34 (m, 3H), 6.84 (d, J=6.5 Hz, 1H),5.15-5.08 (m, 1H), 3.45 (s, 3H), 3.00-2.94 (m, 2H), 2.47-2.28 (m, 1H),2.25-2.13 (m, 1H); LC-MS (method A): [M−H₂O+H]⁺=362.9, Rt=2.33 min; HPLC(method A): purity >99.8%, Rt=2.78 min; chiral SFC (method B): >99% ee,Rt=3.52 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-1-(3-fluorophenyl)-3-methanesulfonyl-6,7-dihydro-4H-2-benzothiophen-4-ol(37a)

Colorless solid prepared according to general procedure C; ¹H NMR (500MHz, DMSO-d₆): δ=7.56 (td, J=8.1, 6.1 Hz, 1H), 7.49-7.45 (m, 1H),7.44-7.41 (m, 1H), 7.35-7.30 (m, 1H), 6.85-6.80 (m, 1H), 5.15-5.09 (m,1H), 3.45 (s, 3H), 2.99-2.91 (m, 2H), 2.45-2.30 (m, 1H), 2.24-2.14 (m,1H); LC-MS (method A): [M−H₂O+H]⁺=344.9, Rt=2.28 min; HPLC (method A):puritity >99%, Rt=2.71 min; chiral SFC (method B): 98.2% er, Rt=6.37min.

The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-1-(4-fluorophenyl)-3-methanesulfonyl-6,7-dihydro-4H-2-benzothiophen-4-ol(38a)

Colorless solid prepared according to general procedure C; ¹H NMR (400MHz, DMSO-d₆): δ=7.67-7.61 (m, 2H), 7.39-7.32 (m, 2H), 6.81 (d, J=4.6Hz, 1H), 5.15-5.08 (m, 1H), 3.44 (s, 3H), 2.91 (dd, J=8.8, 4.9 Hz, 2H),2.47-2.29 (m, 1H), 2.24-2.12 (m, 1H); LC-MS (method A): [M−H₂O+H]=344.9,Rt=2.72 min; HPLC (method A): purity >99%, Rt=2.72 min; chiral SFC(method C): >99% ee, Rt=5.09 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(1,3-dimethyl-1H-pyrazol-4-yI)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(39a)

Colorless solid prepared according to general procedure B; ¹H NMR (400MHz, DMSO-d₆): δ=8.08 (s, 1H), 6.78 (d, J=6.6 Hz, 1H), 5.12-5.05 (m,1H), 3.81 (s, 3H), 3.41 (s, 3H), 2.87-2.71 (m, 2H), 2.47-2.31 (m, 1H),2.28 (s, 3H), 2.26-2.12 (m, 1H); LC-MS (method A): [M+H]⁺=362.9, Rt=1.85min; HPLC (method A): purity >99%, Rt=2.17 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(40a)

Colorless solid prepared according to general procedure B; ¹H NMR (400MHz, DMSO-d₆): δ=8.22-8.20 (m, 1H), 7.82 (d, J=0.8 Hz, 1H), 6.78 (d,J=6.7 Hz, 1H), 5.10-5.03 (m, 1H), 3.89 (s, 3H), 3.39 (s, 3H), 2.99-2.90(m, 1H), 2.89-2.78 (m, 1H), 2.49-2.32 (m, 1H), 2.27-2.14 (m, 1H); LC-MS(method A): [M+H]⁺=348.9, Rt=1.82 min; HPLC (method A): purity 99.1%,Rt=2.12 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(3,4-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(41a)

Colorless solid prepared according to general procedure C; ¹H NMR (400MHz, DMSO-d₆): δ=7.80-7.73 (m, 1H), 7.64-7.55 (m, 1H), 7.48-7.42 (m,1H), 6.88 (d, J=6.5 Hz, 1H), 5.15-5.07 (m, 1H), 3.45 (s, 3H), 2.93 (dd,J=8.8, 4.9 Hz, 2H), 2.47-2.26 (m, 1H), 2.25-2.13 (m, 1H); LC-MS (methodA): [M−H₂O+H]⁺=362.9, Rt=2.36 min; HPLC (method A): purity 99.2%,Rt=2.91 min; chiral SFC (method C): 97.9% er, Rt=4.57 min.

The (4R)-enantiomer has been obtained analogously.

3-[(4S-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-5-fluorobenzonitrile(42a)

Colorless solid prepared according to general procedure C; ¹H NMR (400MHz, DMSO-d₆): δ=8.02-7.97 (m, 2H), 7.92-7.87 (m, 1H), 6.92 (d, J=6.4Hz, 1H), 5.16-5.08 (m, 1H), 3.46 (s, 3H), 2.98 (dd, J=8.7, 4.9 Hz, 2H),2.46-2.27 (m, 1H), 2.27-2.13 (m, 1H); LC-MS (method A):[M−H₂O+H]⁺=369.8, Rt=2.24 min; HPLC (method A): purity >99.9%, Rt=2.75min; chiral SFC (method C): 97.2% er, Rt=3.71 min.

The (4R)-enantiomer has been obtained analogously.

4-[(4S-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrrole-2-carbonitrile(43a)

Colorless solid prepared according to general procedure B; ¹H NMR (400MHz, DMSO-d₆): δ=7.71-7.68 (m, 1H), 7.33 (d, J=1.9 Hz, 1H), 6.79 (d,J=6.5 Hz, 1H), 5.10-5.03 (m, 1H), 3.81 (s, 3H), 3.40 (s, 3H), 3.00-2.91(m, 1H), 2.90-2.79 (m, 1H), 2.47-2.32 (m, 1H), 2.26-2.14 (m, 1H); LC-MS(method A): [M−H₂O+H]=354.9, Rt=2.11 min; HPLC (method A): purity 96.9%,Rt=2.55 min.

The (4R)-enantiomer has been obtained analogously.

4-[(4S-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrrole-2-carbonitrile(44a)

Colorless solid prepared according to general procedure C; ¹H NMR (400MHz, DMSO-d₆): δ=8.17 (dd, J=2.0, 1.3 Hz, 1H), 8.11 (t, J=1.5 Hz, 1H),8.04 (t, J=1.8 Hz, 1H), 6.93 (d, J=6.4 Hz, 1H), 5.16-5.08 (m, 1H), 3.46(s, 3H), 2.99-2.94 (m, 2H), 2.45-2.26 (m, 1H), 2.26-2.13 (m, 1H); LC-MS(method A): [M−H₂O+H]⁺=385.8, Rt=2.35 min; HPLC (method A): purity98.9%, Rt=2.89 min; chiral SFC (method C): 97.9% ee, Rt=4.57 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(45a)

Colorless solid prepared according to general procedure B; ¹H NMR (400MHz, DMSO-d₆): δ=7.59 (dt, J=8.7, 2.1 Hz, 1H), 7.56-7.53 (m, 1H),7.54-7.49 (m, 1H), 6.90 (d, J=6.5 Hz, 1H), 5.15-5.08 (m, 1H), 3.45 (s,3H), 2.96 (dd, J=8.7, 4.9 Hz, 2H), 2.44-2.27 (m, 1H), 2.25-2.13 (m, 1H);LC-MS (method A): [M−H₂O+H]⁺=378.8, Rt=2.51 min; HPLC (method A): purity98.8%, Rt=3.09 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(46a)

Colorless solid prepared according to general procedure B; ¹H NMR (400MHz, DMSO-d₆): δ=7.17-7.15 (m, 1H), 6.92 (d, J=6.5 Hz, 1H), 5.16-5.09(m, 1H), 3.91 (s, 3H), 3.48 (s, 3H), 2.82-2.74 (m, 2H), 2.48-2.28 (m,1H), 2.25-2.13 (m, 1H); LC-MS (method A): [M+H]⁺=416.8, Rt=2.32 min;HPLC (method A): purity 98.1%, Rt=2.80 min.

The (4R)-enantiomer has been obtained analogously.

Following examples are prepared analogously:

(4S)-5,5-difluoro-3-methanesulfonyl-1-(1-methyl-1H-pyrazol-5-yl)-4H,5H,6H-cyclopenta[c]thiophen-4-ol(47a)

Prepared according to general procedure A; ¹H NMR (300 MHz, DMSO-d₆):δ=7.58 (d, 1H), 6.83 (s, 1H), 6.68 (d, 1H), 5.15 (m, 1H), 3.96 (s, 3H),3.42 (d, 5H); LC-MS (Method D): Rt=0.88 min, [M+H]⁺=335.0; HPLC (methodD): purity 98.0%, Rt=4.6 min; chiral HPLC (method D): 99.3% ee, Rt=2.20min.

The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4H,5H,6H-cyclopenta[c]thiophen-4-ol(48a)

Prepared according to general procedure A; ¹H NMR (300 MHz, DMSO-d₆):δ=6.94 (s, 1H), 5.23 (dd, 1H), 4.04 (s, 3H), 3.48-3.34 (m, 5H); LC-MS(Method E): Rt=2.52 min, [M+H]⁺=403.0; HPLC (method D): purity 97.9%,Rt=6.11 min; chiral HPLC (method D): 99.9% ee, Rt=1.87 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(1,3-dimethyl-1H-pyrazol-5-yl)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol(49a)

Prepared according to general procedure A; ¹H NMR (300 MHz, DMSO-d6):δ=6.82 (d, 1H), 6.44 (s, 1H), 5.13 (m, 1H), 3.86 (s, 3H), 3.46 (s, 3H),3.39 (m, 2H), 2.18 (s, 3H); LC-MS (Method D): Rt=0.942 min,[M+H]⁺=349.0; HPLC (method D): purity 99.9%, Rt=4.93 min; chiral HPLC(method D): 99.9% ee, Rt=3.38 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(1,3-dimethyl-1H-pyrazol-5-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(50a)

The product was prepared according to general procedure B; ¹H NMR (500MHz, DMSO-d₆): δ=6.85 (d, J=6.5 Hz, 1H), 6.37 (s, 1H), 5.14-5.08 (m,1H), 3.74 (s, 3H), 3.46 (s, 3H), 2.80-2.70 (m, 2H), 2.45-2.31 (m, 1H),2.25-2.13 (m, 1H), 2.19 (s, 3H); LC-MS (method A): [M+H]⁺=362.9, Rt=1.91min; HPLC (method A): purity 94.1%, Rt=2.29 min.

The (4R)-enantiomer has been obtained analogously.

5-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrazole-3-carbonitrile(51a)

The product was prepared according to general procedure B; ¹H NMR (500MHz, DMSO-d₆): δ=7.38 (s, 1H), 6.92 (d, J=6.6 Hz, 1H), 5.15-5.09 (m,1H), 3.92 (s, 3H), 3.49-3.47 (m, 3H), 2.82-2.70 (m, 2H), 2.45-2.30 (m,1H), 2.24-2.14 (m, 1H); LC-MS (method A): [M+H]⁺=373.9, Rt=2.02 min;HPLC (method A): purity 99.6%, Rt=2.48 min.

The (4R)-enantiomer has been obtained analogously.

3-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrazole-4-carbonitrile(52a)

4-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrazole-3-carbonitrile(53a)

3-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrazole-5-carbonitrile(54a)

The product was prepared according to general procedure B; ¹H NMR (500MHz, DMSO-d₆): δ=7.59 (s, 1H), 6.82 (d, J=6.7 Hz, 1H), 5.12-5.06 (m,1H), 4.08 (s, 3H), 3.42 (s, 3H), 3.17-3.08 (m, 1H), 2.97-2.87 (m, 1H),2.53-2.35 (m, 1H), 2.30-2.17 (m, 1H); LC-MS (method A): [M+H]⁺=373.9,Rt=2.08 min; HPLC (method A): purity 100.0%, Rt=2.55 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(2,6-difluoropyridin-4-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(55a)

The product was prepared according to general procedure B; ¹H NMR (500MHz, DMSO-d₆): δ=7.47 (s, 2H), 6.91 (d, J=6.5 Hz, 1H), 5.16-5.10 (m,1H), 3.48 (s, 3H), 3.13-3.00 (m, 2H), 2.46-2.31 (m, 1H), 2.27-2.17 (m,1H); LC-MS (method A): [M+H]⁺=381.8, Rt=2.22 min; HPLC (method A):purity 100.0%, Rt=2.75 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(5-chloropyridin-3-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(56a)

The product was prepared according to general procedure B; ¹H NMR (500MHz, DMSO-d₆): δ=8.74-8.74 (m, 1H), 8.73-8.72 (m, 1H), 8.22 (t, J=2.1Hz, 1H), 6.87 (d, J=6.5 Hz, 1H), 5.16-5.10 (m, 1H), 3.46 (s, 3H), 2.97(dd, J=8.7, 4.9 Hz, 2H), 2.45-2.30 (m, 1H), 2.24-2.15 (m, 1H); LC-MS(method A): [M+H]⁺=379.8, Rt=2.09 min; HPLC (method A): purity 98.5%,Rt=2.55 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-(5-methylpyridin-3-yl)-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(57a)

The product was prepared according to general procedure B; ¹H NMR (500MHz, DMSO-d₆): δ=8.59-8.57 (m, 1H), 8.52-8.50 (m, 1H), 7.87-7.85 (m,1H), 6.84 (d, J=6.5 Hz, 1H), 5.16-5.10 (m, 1H), 3.45 (s, 3H), 2.96 (dd,J=8.8, 4.8 Hz, 2H), 2.44-2.31 (m, 1H), 2.38-2.37 (m, 3H), 2.24-2.15 (m,1H); LC-MS (method A): [M+H]⁺=359.9, Rt=1.73 min; HPLC (method A):purity 99.2%, Rt=1.98 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-1-(5-fluoropyridin-3-yl)-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(58a)

The product was prepared according to general procedure B; ¹H NMR (500MHz, DMSO-d₆): δ=8.70-8.69 (m, 1H), 8.68-8.66 (m, 1H), 8.08-8.05 (m,1H), 6.87 (d, J=6.5 Hz, 1H), 5.16-5.11 (m, 1H), 3.46 (s, 3H), 2.98 (dd,J=8.7, 4.9 Hz, 2H), 2.45-2.30 (m, 1H), 2.25-2.15 (m, 1H); LC-MS (methodA): [M+H]⁺=363.9, Rt=1.95 min; HPLC (method A): purity 100.0%, Rt=2.35min.

The (4R)-enantiomer has been obtained analogously.

5-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]pyridine-3-carbonitrile(59a)

The product was prepared according to general procedure B; ¹H NMR (400MHz, DMSO-d₆): δ=9.10 (d, J=1.9 Hz, 1H), 9.05 (d, J=2.2 Hz, 1H),8.62-8.60 (m, 1H), 6.89 (d, J=6.5 Hz, 1H), 5.17-5.10 (m, 1H), 3.47 (s,3H), 3.02-2.96 (m, 2H), 2.45-2.28 (m, 1H), 2.26-2.13 (m, 1H); LC-MS(method A): [M+H]⁺=370.9, Rt=1.90 min; HPLC (method A): purity 95.6%,Rt=2.31 min.

The (4R)-enantiomer has been obtained analogously.

6-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-4-methylpyridine-2-carbonitrile(60a)

(4S)-1-(6-chloro-5-fluoropyridin-3-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(61a)

The product was prepared according to general procedure B; ¹H NMR (400MHz, DMSO-d₆): δ=8.53-8.51 (m, 1H), 8.28 (dd, J=9.4, 2.1 Hz, 1H), 6.88(d, J=6.5 Hz, 1H), 5.16-5.09 (m, 1H), 3.46 (s, 3H), 3.01-2.96 (m, 2H),2.46-2.28 (m, 1H), 2.26-2.14 (m, 1H); LC-MS (method A): [M+H]⁺=397.8,Rt=2.25 min; HPLC (method A): purity 100.0%, Rt=2.77 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-3-methanesulfonyl-1-[5-(trifluoromethyl)pyridin-3-yl]-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(62a)

The product was prepared according to general procedure B; ¹H NMR (400MHz, DMSO-d₆): δ=9.10-9.08 (m, 1H), 9.08-9.06 (m, 1H), 8.46-8.43 (m,1H), 6.89 (d, J=6.4 Hz, 1H), 5.18-5.11 (m, 1H), 3.47 (s, 3H), 3.02-2.95(m, 2H), 2.48-2.28 (m, 1H), 2.26-2.13 (m, 1H); LC-MS (method A):[M+H]⁺=413.8, Rt=2.18 min; HPLC (method A): purity 100.0%, Rt=2.67 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(2-chloro-6-fluoropyridin-4-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(63a)

The product was prepared according to general procedure B; ¹H NMR (400MHz, DMSO-d₆): δ=7.78-7.75 (m, 1H), 7.54-7.52 (m, 1H), 6.91 (d, J=6.5Hz, 1H), 5.16-5.09 (m, 1H), 3.47 (s, 3H), 3.12-2.98 (m, 2H), 2.45-2.31(m, 1H), 2.28-2.15 (m, 1H); LC-MS (method A): [M+H]⁺=397.8, Rt=2.28 min;HPLC (method A): purity 100.0%, Rt=2.82 min.

The (4R)-enantiomer has been obtained analogously.

6-chloro-4-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]pyridine-2-carbonitrile(64a)

The product was prepared according to general procedure B; ¹H NMR (500MHz, DMSO-d₆): δ=8.37 (d, J=1.5 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 6.93(d, J=6.5 Hz, 1H), 5.15-5.10 (m, 1H), 3.48 (s, 3H), 3.12-3.02 (m, 2H),2.44-2.30 (m, 1H), 2.27-2.17 (m, 1H); LC-MS (method A): [M+H]⁺=404.8,Rt=2.24 min; HPLC (method A): purity 97.4%, Rt=2.79 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-1-(5-chloro-6-methoxypyridin-3-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(65a)

The product was prepared according to general procedure B; ¹H NMR (500MHz, DMSO-d₆): δ=8.34 (d, J=2.2 Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 6.84(d, J=6.5 Hz, 1H), 5.15-5.09 (m, 1H), 4.01 (s, 3H), 3.44 (s, 3H), 2.93(dd, J=9.0, 5.0 Hz, 2H), 2.45-2.29 (m, 1H), 2.23-2.14 (m, 1H); LC-MS(method A): [M+H]⁺=409.9, Rt=2.35 min; HPLC (method A): purity 99.4%,Rt=2.91 min.

The (4R)-enantiomer has been obtained analogously.

(4S)-5,5-difluoro-1-(3-fluorophenyl)-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol(66a)

The product was prepared according to general procedure B; ¹H NMR (500MHz, DMSO-d₆): δ=7.56 (td, J=8.1, 6.1 Hz, 1H), 7.49-7.45 (m, 1H),7.44-7.41 (m, 1H), 7.35-7.30 (m, 1H), 6.85-6.80 (m, 1H), 5.15-5.09 (m,1H), 3.45 (s, 3H), 2.99-2.91 (m, 2H), 2.45-2.30 (m, 1H), 2.24-2.14 (m,1H); LC-MS (method A): [M−H₂O+H]⁺=344.9, Rt=2.28 min; HPLC (method A):purity 100.0%, Rt=2.71 min.

The (4R)-enantiomer has been obtained analogously.

Synthesis of Compounds 67a and 68a

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed compound 4 (2.00 g, 9.18 mmol, 1.00equiv, 95%), tetrahydrofuran (15.0 mL, 175.89 mmol, 19.17 equiv, 95%),(methylsulfanyl)sodium (812 mg, 11.01 mmol, 1.20 equiv, 95%). Theresulting solution was stirred for 2 h at 25° C. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:10). Thecollected fractions were combined and concentrated under vacuum. Thisresulted in 1.6 g (77%) of1-chloro-3-(methylsulfanyl)-4H,5H,6H-cyclopenta[c]thiophen-4-one as ared solid.

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed1-chloro-3-(methylsulfanyl)-4H,5H,6H-cyclopenta[c]thiophen-4-one (200mg, 0.88 mmol, 1.0 equiv, 96%), dichloromethane (5 mL, 74.72 mmol, 85equiv, 95%), m-CPBA (638 mg, 3.51 mmol, 4.00 equiv, 95%). The resultingsolution was stirred for 2 h at 25° C. The resulting solution wasextracted with 4×10 mL of ethyl acetate and the organic layers combined.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1/5). The collected fractions were combined andconcentrated under vacuum. This resulted in 220 mg (90%) of1-chloro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one as awhite solid.

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed1-chloro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one (4.00 g,15.412 mmol, 1.00 equiv, 96.6%), ethane-1,2-diol (1.51 g, 23.118 mmol,1.50 equiv, 95%), TsOH (0.56 g, 3.1 mmol, 0.20 equiv, 95%), toluene (100mL, 939.9 mmol, 60.98 equiv, 100%). The resulting solution was stirredfor 16 hr at 125° C. The resulting mixture was concentrated. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:3). This resulted in 4 g (85.2%) of1-chloro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2-[1,3]dioxolane]as a yellow solid.

Into a 30-mL flask purged and maintained with an inert atmosphere ofnitrogen, was placed1-chloro-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2-[1,3]dioxolane](500 mg, 1.671 mmol, 1 equiv, 98.5%), (3-chloro-5-fluorophenyl)boronicacid (442.4 mg, 2.410 mmol, 1.44 equiv, 95%), Pd(PPh3)4 (291.7 mg, 0.240mmol, 0.14 equiv, 95%), Na₂CO₃ (359.3 mg, 8148 mmol, 4876 equiv, 95%),dioxane (10 mL, 112.14 mmol, 67.11 equiv, 95%), H₂O (1 mL, 52.733 mmol,31.56 equiv, 95%). The resulting solution was stirred for 3 hr at 80° C.The resulting mixture was concentrated under vacuum. The crude product(515 mg) was purified by Flash-Prep. This resulted in 0.515 g (62.4%) of1-(3-chloro-5-fluorophenyl)-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2-[1,3]dioxolane]as a yellow solid.

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed1-(3-chloro-5-fluorophenyl)-3-methanesulfonyl-5,6-dihydrospiro[cyclopenta[c]thiophene-4,2-[1,3]dioxolane](510mg, 0.816 mmol, 1 equiv, 62.2%), DCM (4 mL, 59.774 mmol, 73.27 equiv,95%), TFA (140 uL, 1.79 mol, 95%). The resulting solution was stirredfor 60 min at 25° C. The resulting mixture was concentrated undervacuum. The residue was dissolved in 30 mL of EtOAc. The resultingmixture was washed with 30 ml of NaHCO₃ and 1×30 mL of NaCl solution.The mixture was dried over anhydrous sodium sulfate and concentratedunder vacuum. This resulted in 360 mg (61.4%) of1-(3-chloro-5-fluorophenyl)-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-oneas a yellow solid.

Into a 30 mL microwave tube were added1-(3-chloro-5-fluorophenyl)-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one(300 mg, 0.424 mmol, 1 equiv, 48.7%), methanol (10 mg, 0.296 mmol, 0.7equiv, 95%), selectfluor (705 mg, 1.891 mmol, 4.46 equiv, 95%) and H₂SO₄(0.1 mg, 1.782 mmol, 4.21 equiv, 95%) at 60° C. The resulting mixturewas stirred for 90 min at 60° C. under nitrogen atmosphere. The residuewas dissolved in EtOAc (50 mL). The resulting mixture was washed with2×30 mL of NaCl solution and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by Prep-TLC (PE/EtOAc 5:1) to afford1-(3-chloro-5-fluorophenyl)-5-fluoro-3-methanesulfonyl-4,4-dimethoxy-4H,5H,6H-cyclopenta[c]thiophene(130 mg, 62.9%) as a yellow oil. Into a 10 mL microwave tube were added1-(3-chloro-5-fluorophenyl)-5-fluoro-3-methanesulfonyl-4,4-dimethoxy-4H,5H,6H-cyclopenta[c]thiophene(10 mg, 0.020 mmol, 1 equiv, 83.8%), DCM (2.5 mL) and TFA (170 uL, 2.29mol, 95%) at room temperature. The resulting mixture was stirred for 60min at room temperature under nitrogen atmosphere and was thenconcentrated under reduced pressure. The residue was dissolved in EtOAc(10 mL). The resulting mixture was washed with 1×5 mL of NaHCO₃. Theresulting mixture was washed with 1×5 mL of NaCl and dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure. The resulting mixture was concentrated under reducedpressure. This resulted in1-(3-chloro-5-fluorophenyl)-5-fluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one(10.9 mg, 89.3%) as a yellow solid.

To obtain compound 67a, into a 25-mL round-bottom flask purged andmaintained with an inert atmosphere of nitrogen, was placed1-(3-chloro-5-fluorophenyl)-5-fluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one(150.00 mg, 0.332 mmol, 1.00 equiv, 80.3%), DCM (10.00 mL, 117.739 mmol,473.78 equiv, 100%), HCOOH (48.26 mg, 0.996 mmol, 3 equiv, 95%), TEA(70.73 mg, 0.664 mmol, 2 equiv, 95%), RuCl(p-cymene)[(R,R)-Ts-DPEN](22.23 mg, 0.033 mmol, 0.1 equiv, 95%). The resulting solution wasstirred for 5 hr at 0° C. The pH value of the solution was adjusted to 7with NaHCO₃. The resulting solution was extracted with 3×30 mL of ethylacetate dried over anhydrous sodium sulfate and concentrated. The crudeproduct was purified by Prep-HPLC followed by chiral SFC to obtaincompound 67a as a white solid. The compound exhibited a melting point of138-140° C.

To prepare a sufficient amount of material to also access compound 68a,to a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was added1-(3-chloro-5-fluorophenyl)-5-fluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-one(150.00 mg, 0.332 mmol, 1.00 equiv, 80.3%), DCM (10.00 mL, 117.739 mmol,473.78 equiv, 100%), HCOOH (48.26 mg, 0.996 mmol, 3 equiv, 95%), TEA(70.73 mg, 0.664 mmol, 2 equiv, 95%), RuCl(p-cymene)[(R,R)-Ts-DPEN](22.23 mg, 0.033 mmol, 0.1 equiv, 95%). The resulting solution wasstirred for 5 hr at 0° C. The pH value of the solution was adjusted to 7with NaHCO₃. The resulting solution was extracted with 3×30 mL of ethylacetate dried over anhydrous sodium sulfate and concentrated. The crudeproduct was purified by Prep-HPLC, followed by chiral SFC to obtaincompound 68a as a white solid. The compound exhibited a melting point of135-137° C.

(4S,5S)-1-(3-chloro-5-fluorophenyl)-5-fluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol(67a)

¹H NMR (300 MHz, Methanol-d₄, ppm): δ=7.46 (s, 1H), 7.35-7.31 (m, 2H),5.40-5.32 (m, 1H), 5.24-5.14 (m, 1H), 3.56-3.49 (m, 1H), 3.34 (S, 3H),3.19-2.97 (m, 1H); LC-MS (Method D): Rt=1.24 min, [M+44]⁺=408.7; HPLC(method D): purity 99.6%, Rt=6.42 min; Chiral SFC (Method G): Rt=2.30min, er=94.9%.

(4S,5R)-1-(3-chloro-5-fluorophenyl)-5-fluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol(68a)

¹H NMR (300 MHz, Methanol-d₄, ppm): δ=7.46 (s, 1H), 7.41-7.27 (m, 2H),5.52-5.27 (m, 1H), 5.24-5.18 (m, 1H), 3.69-3.40 (m, 1H), 3.35 (s, 3H),3.16-3.00 (m, 1H); LC-MS (Method D): Rt=1.30 min, [M+44]⁺=408.7; HPLC(method D with runtime stretched to 21 min): purity 97.0%, Rt=14.56 min;Chiral SFC (Method G): Rt=1.92 min, er=100%.

The following examples relate to medicaments:

EXAMPLE A: INJECTION VIALS

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B: SUPPOSITORIES

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C: SOLUTION

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D: OINTMENT

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E: TABLETS

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F: DRAGEES

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G: CAPSULES

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H: AMPOULES

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1: A compound of the formula I:

in which R¹ denotes A, Ar, Cyc, Het, COA, or CN, R² denotes SO₂A, SOA,SA, SO₂NHA, SO₂NA₂, S(═NH,═O)A, S(═NH)₂A, NO₂, Hal, CN, A, Het¹, COOH,or COOA, R³ denotes H or Hal, R⁴ denotes H or Hal, A denotes unbranchedor branched alkyl having 1-6 C-atoms, in which 1-7 H atoms may bereplaced by OH, F, Cl, and/or Br, and/or in which one or twonon-adjacent CH₂ groups may be replaced by O and/or NH groups, Cycdenotes cyclic alkyl with 3, 4, 5, 6, or 7 C-atoms, Ar denotes phenyl,which is unsubstituted or mono-, di-, or trisubstituted by Hal, A,[C(R⁵)₂]_(p)OR⁵, O[C(R⁵)₂]_(p)OR⁵, [C(R⁵)₂]_(p)N(R⁵)₂,O[C(R⁵)₂]_(p)N(R⁵)₂, [C(R⁵)₂]_(p)Het¹, NO₂, CN, [C(R⁵)₂]_(p)COOR⁵,O[C(R⁵)₂]_(p)COOR⁵, CON(R⁵)₂, NR⁵COA, NR⁵SO₂A, SO₂N(R⁵)₂, S(O)₂A,COHet¹, O[C(R⁵)₂]_(p)Het¹, NHCOOA, NHCON(R⁵)₂, NHCOO[C(R⁵)₂]_(m)N(R⁵)₂,NHCOO[C(R⁵)₂]_(p)Het¹, NHCONH[C(R⁵)₂]_(m)N(R⁵)₂, NHCONH[C(R⁵)₂]_(p)Het¹,OCONH[C(R⁵)₂]_(m)N(R⁵)₂, OCONH[C(R⁵)₂]_(p)Het¹, S(O)₂Het¹, and/or COA,Het denotes a mono- or bicyclic aromatic, unsaturated or saturatedheterocycle having 1 to 4 N, O, and/or S atoms, which may beunsubstituted or mono-, di-, or trisubstituted by Hal, A, NH₂, NHA, NA₂,COOH, COOA, CONH₂, CONHA, CONA₂, CONHAr, S(O)_(m)A, NHCH₂Ar¹, CN, OH,and/or OA, Het¹ denotes a mono- or bicyclic aromatic, unsaturated orsaturated heterocycle having 1 to 4 N, O, and/or S atoms, which may beunsubstituted or mono-, di-, or trisubstituted by Hal, A, COOA, NH₂,NHA, and/or NA₂, Ar¹ denotes phenyl which is unsubstituted or mono-,di-, or trisubstituted by Hal, A, OH, and/or OA, R⁵ denotes H or alkylwith 1, 2, 3 or 4 C-atoms, Hal denotes F, Cl, Br, or I, n denotes 1, 2,or 3, m denotes 1, 2, or 3, p denotes 0, 1, 2, 3, or 4, andpharmaceutically acceptable salts, tautomers, and stereoisomers thereof,including mixtures thereof in all ratios. 2: The compound according toclaim 1, in which: R¹ denotes Ar or Het, and pharmaceutically acceptablesolvates, salts, tautomers, and stereoisomers thereof, includingmixtures thereof in all ratios. 3: The compound according to claim 1, inwhich: R² denotes SO₂A, and pharmaceutically acceptable salts,tautomers, and stereoisomers thereof, including mixtures thereof in allratios. 4: The compound according to claim 1, in which: R³ denotes H orF, R⁴ denotes H or F, and pharmaceutically acceptable salts, tautomers,and stereoisomers thereof, including mixtures thereof in all ratios. 5:The compound according to claim 1, in which: A denotes unbranched orbranched alkyl having 1-6 C-atoms, in which 1-5 H atoms may be replacedby OH and/or F, and pharmaceutically acceptable salts, tautomers, andstereoisomers thereof, including mixtures thereof in all ratios. 6: Thecompound according to claim 1, in which: Ar denotes phenyl, which isunsubstituted or mono-, di-, or trisubstituted by Hal and/or CN, andpharmaceutically acceptable salts, tautomers, and stereoisomers thereof,including mixtures thereof in all ratios. 7: The compound according toclaim 1, in which: Het denotes a monocyclic aromatic heterocycle having1 to 4 N, O, and/or S atoms, which may be unsubstituted or mono-, di-,or trisubstituted by Hal, A, CN, OH, and/or OA, and pharmaceuticallyacceptable salts, tautomers, and stereoisomers thereof, includingmixtures thereof in all ratios. 8: The compound according to claim 1, inwhich: Het denotes pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, orpyrimidinyl, each of which may be unsubstituted or mono-, di- ortrisubstituted by Hal, OA, OH, A, and/or CN, and pharmaceuticallyacceptable salts, tautomers, and stereoisomers thereof, includingmixtures thereof in all ratios. 9: The compound according to claim 1, inwhich: R¹ denotes Ar or Het, R² denotes SO₂A, R³ denotes H or Hal, R⁴denotes H or Hal, A denotes unbranched or branched alkyl having 1-6C-atoms, in which 1-5 H atoms may be replaced by OH and/or F, Ar denotesphenyl, which is unsubstituted or mono-, di-, or trisubstituted by Haland/or CN, Het denotes a monocyclic aromatic heterocycle having 1 to 4N, O, and/or S atoms, which may be unsubstituted or mono-, di-, ortrisubstituted by Hal, A, CN, OH, and/or OA, Hal denotes F, Cl, Br, orI, n denotes 1, 2, or 3, and pharmaceutically acceptable salts,tautomers, and stereoisomers thereof, including mixtures thereof in allratios. 10: The compound according to claim 1, selected from the thefollowing: No. Structure 13a(4S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol 23a(S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 25a(4S)-5,5-difluoro-3-methanesulfonyl-1-phenyl-4H,6H-cyclopenta[c]thiophen-4-ol 26a(4S)-1-(3,5-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol 27a(4S)-5,5-difluoro-1-(2-fluorophenyl)-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol 28a(4S)-5,5-difluoro-1-(3-fluorophenyl)-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol 29a(4S)-5,5-difluoro-1-(4-fluorophenyl)-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol 30a(4S)-1-(3,4-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-4-ol 31a4-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,6H-yclopenta[c]thiophen-1-yl]-2-fluorobenzonitrile 32a3-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-1-yl]benzonitrile 33a3-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-1-yl]-5-fluorobenzonitrile 34a(4S)-3-chloro-5-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4H,6H-cyclopenta[c]thiophen-1-yl]benzonitrile 35a(4S)-5,5-difluoro-3-methanesulfonyl-1-(1-methyl-1H-pyrazol-4-yl)-4H,5H,6H-cyclopenta[c]thiophen-4-ol 36a(4R)-3-methanesulfonyl-1-phenyl-4,5,6,7-tetrahydro-2- benzothiophen-4-ol37a (4S)-5,5-difluoro-1-(3-fluorophenyl)-3-methanesulfonyl-6,7-dihydro-4H-2-benzothiophen-4-ol 38a(4S)-5,5-difluoro-1-(4-fluorophenyl)-3-methanesulfonyl-6,7-dihydro-4H-2-benzothiophen-4-ol 39a(4S)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 40a(4S)-5,5-difluoro-3-methanesulfonyl-1-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 41a(4S)-1-(3,4-difluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 42a3-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-5-fluorobenzonitrile 43a4-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrrole-2-carbonitrile 44a4-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrrole-2-carbonitrile 45a(4S)-1-(3-chloro-5-fluorophenyl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 46a(4S)-5,5-difluoro-3-methanesulfonyl-1-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 47a(4S)-5,5-difluoro-3-methanesulfonyl-1-(1-methyl-1H-pyrazol-5-yl)-4H,5H,6H-cyclopenta[c]thiophen-4-ol 48a(4S)-5,5-difluoro-3-methanesulfonyl-1-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4H,5H,6H-cyclopenta[c]thiophen-4-ol 49a(4S)-1-(1,3-dimethyl-1H-pyrazol-5-yl)-5,5-difluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol 50a(4S)-1-(1,3-dimethyl-1H-pyrazol-5-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 51a5-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrazole-3-carbonitrile 52a3-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrazole-4-carbonitrile 53a4-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrazole-3-carbonitrile 54a3-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-1-methyl-1H-pyrazole-5-carbonitrile 55a(4S)-1-(2,6-difluoropyridin-4-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 56a(4S)-1-(5-chloropyridin-3-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 57a(4S)-5,5-difluoro-3-methanesulfonyl-1-(5-methylpyridin-3-yl)-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 58a(4S)-5,5-difluoro-1-(5-fluoropyridin-3-yl)-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 59a5-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]pyridine-3-carbonitrile 60a6-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]-4-methylpyridine-2-carbonitrile 61a(4S)-1-(6-chloro-5-fluoropyridin-3-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 62a(4S)-5,5-difluoro-3-methanesulfonyl-1-[5-(trifluoromethyl)pyridin-3-yl]-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 63a(4S)-1-(2-chloro-6-fluoropyridin-4-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 64a6-chloro-4-[(4S)-5,5-difluoro-4-hydroxy-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-1-yl]pyridine-2-carbonitrile 65a(4S)-1-(5-chloro-6-methoxypyridin-3-yl)-5,5-difluoro-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 66a(4S)-5,5-difluoro-1-(3-fluorophenyl)-3-methanesulfonyl-4,5,6,7-tetrahydro-2-benzothiophen-4-ol 67a(4S,5S)-1-(3-chloro-5-fluorophenyl)-5-fluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol 68a(4S,5R)-1-(3-chloro-5-fluorophenyl)-5-fluoro-3-methanesulfonyl-4H,5H,6H-cyclopenta[c]thiophen-4-ol

and pharmaceutically acceptable solvates, salts, tautomers, andstereoisomers thereof, including mixtures thereof in all ratios. 11: Aprocess for preparation of the compound according to claim 1 andpharmaceutically acceptable salts, solvates, tautomers, andstereoisomers thereof, the process comprising: a) reacting a compound ofthe formula II:

in which R², R³, R⁴, and n have the meanings indicated in claim 1, and Xis F, Cl, Br or I, with a compound of formula III:L-R¹  III, in which R¹ has the meaning indicated in claim 1, and Ldenotes H, a boronic acid or a boronic acid ester group, or b) reactinga compound of the formula IV:

in which R¹, R², R³, R⁴, and n have the meanings indicated in claim 1,with NaBH₄, and/or converting a base or acid of the formula I into oneof the base's or acid's salts. 12: A medicament, comprising: at leastone compound according to claim 1 and/or pharmaceutically acceptablesalts, solvates, tautomers, and stereoisomers thereof, includingmixtures thereof in all ratios, and optionally a pharmaceuticallyacceptable carrier, excipient, or vehicle. 13: A method for treatment ofcancer and von Hippel-Lindau disease, comprising: administering thecompound according to claim 1 and pharmaceutically acceptable salts,solvates, tautomers, and stereoisomers thereof, including mixturesthereof in all ratios, to a patient in need thereof. 14: The processaccording to claim 13, wherein the cancer is selected from the groupconsisting of cancer of head, neck, eye, mouth, throat, esophagus,bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach,prostate, urinary bladder, uterine, cervix, breast, ovaries, testiclesor other reproductive organs, skin, thyroid, blood, lymph nodes, kidney,liver, pancreas, brain, central nervous system, solid tumors,blood-borne tumors, glioblastoma, renal cell carcinoma, and clear cellrenal cell carcinoma. 15: A medicament, comprising: at least onecompound according to claim 1 and/or pharmaceutically acceptable salts,solvates, and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient. 16: Akit, comprising: (a) a first pack, comprising an effective amount of thecompound according to claim 1 and/or pharmaceutically acceptable salts,solvates, salts, and stereoisomers thereof, including mixtures thereofin all ratios, and (b) a second pack, comprising an effective amount ofa further medicament active ingredient.